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ChEMBL_66880 (CHEMBL676071) Dissociation constant for peptide inhibitor binding to HER2 receptor Fluorescence Assays for Determination of Binding Affinity. Binding was detected as a change in the intrinsic tryptophan fluorescence of the PI3K upon the addition of inhibitor. The inhibitor was incubated with the protein for at least 15 min before the fluorescence intensity was measured. Fluorescence data were acquired for 30 s and averaged for each concentration of inhibitor. The background fluorescence of a solution without inhibitor was subtracted from each measurement. Data were then fitted to a binding equation to obtain dissociation constants. ChEMBL_158026 (CHEMBL768619) Association rate constant for the interaction between inhibitor and HIV-1 protease Inhibition assay The inhibitor was screened against recombinant PLproSARS and PLproCoV2 at 37°Cin the assay buffer as described above. For steady state measurement the enzymes were incubated for 60min at 37°C with an inhibitor before adding the substrate to the wells. Eight different inhibitor concentrations were used. Value of the concentration of the inhibitor that achieved 50% inhibition (IC50) was taken from the dependence ofthe hydrolysis velocity on the logarithm of the inhibitor concentration [I]. Inhibition Assay Inhibition of Rho kinase 2 and Rho kinase 1 activity was determined using the IMAP™ Screening Express Kit (Molecular Devices product number #8073). Rho kinase 2 enzyme (Upstate/Chemicon #14-451), Rho kinase 1 (Upstate/Chemicon #14-601) and Flourescein tagged substrate peptide F1-AKRRRLSSLRA (Molecular Devices product number R7184) was pre-incubated with a test compound for 5 minutes in buffer containing 10 mM Tris-HCl pH 7.2, 10 mM MgCl2, and 0.1% BSA. Following the pre-incubation, 10 μM ATP was added to initiate the reaction. After 60 minutes at room temperature, Molecular Devices IMAP™ binding solution was added to bind phosphorylated substrate. After 30 minutes of incubation in the presence of the IMAP™ beads, the fluorescence polarization was read and the ratio was reported as mP. ChEMBL_2274027 Inhibition of human USP7 using ubiquitin-Rho as substrate incubated for 1 hrs ChEMBL_98402 (CHEMBL706599) Compound was evaluated for the inhibition of Leucine aminopeptidase and the inhibition constant was determined after preincubating the enzyme and inhibitor ChEMBL_98520 (CHEMBL856600) Compound was evaluated for the inhibition of Leucine aminopeptidase and the inhibition constant was determined after preincubating the enzyme and inhibitor ChEMBL_98521 (CHEMBL706541) Compound was evaluated for the inhibition of Leucine aminopeptidase and the inhibition constant was determined after preincubating the enzyme and inhibitor ChEMBL_2437004 Inhibition of LPO (unknown origin)-mediated L-tyrosine nitration incubated for 20 mins in presence of H2O2 and sodium nitrite by RP-HPLC analysis Inhibition Potency Measurements The inhibition potency (IC50) was measured by fluorescent enzymatic assays. The compounds were evaluated for their ability to inhibit the hydrolysis of fluorescence-quenched peptide substrate. The enzyme was incubated with increasing concentration of inhibitor and the fluorescence (ex=328 nm; em=393 nm) was measured for 3 min after the addition of the substrate using a Varian Eclipse fluorimeter. Fitting of hydrolysis rate as a function of inhibitor concentration provided IC50. ChEMBL_432047 (CHEMBL918244) Inhibition of Rho kinase ChEMBL_432392 (CHEMBL915970) Inhibition of Rho kinase ChEBML_1703653 Inhibition of Rho-associated protein kinase 2 (unknown origin) ChEBML_157702 Compound was tested for the inhibition of HIV-1 protease by assaying the cleavage of a fluorescent peptide using HPLC In Vitro Assessment of Peptide Substrate Cleavage by BoNTA-LC Reactions between recombinant BoNTA-LC and fluorescent peptide substrate were carried out in 96-well microplates. Reaction progress was measured continuously by increase in fluorescence at Ex =398 nm, Em=485 nm as the cleavage of the substrate relieved the quenching of DACIA fluorescence by the 2,4-dinitrophenyl-lysine. The initial velocity values for enzymatic cleavage of peptide substrate were plotted against inhibitor concentration. The points were fit by non-linear regression analysis using the graphing program Prism (GraphPad). IC50 is the inhibitor concentration that achieves half-maximal enzyme inhibition. In Vitro Assay The IC50 of the compounds for inhibiting the interaction of a fluorescent NRF2 peptide and the Kelch domain of KEAP1 was determined using fluorescence anisotropy. Kinase assays for IC50 determinations Kinase activity was assayed in reaction buffer containing substrate peptide, enzyme, and inhibitor compound in the presence ATP/[gamma-33P] ATP. 33P incorporation was measured using a Perkin-Elmer Trilux scintillation counter. The IC50 is the inhibitor concentration, which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from 33P labeled ATP to the substrate. ChEMBL_35363 (CHEMBL874110) Compound was evaluated for the inhibition of Aminopeptidase M (AP-M) and the inhibition constant was determined after preincubating the enzyme and inhibitor ChEMBL_197036 (CHEMBL806275) compound was evaluated for the inhibitor constant against human S-adenosyl-L-methionine decarboxylase ChEMBL_461 (CHEMBL615691) The ability of the peptide to inhibit the binding of 50 pM [125I]gastrin releasing peptide to intact S-3T3 cells Enzyme Inhibition Assay IC50 is the concentration of inhibitor that decreases the velocity of the standard assay by 50%. The enzyme, NADPH, and varying concentrations of inhibitor were preincubated for 2 min, and the reaction was initiated by the addition of dihydrofolic acid. Steady state velocities were measured, and IC50 values were calculated from a linear regression plot of the percentage inhibition vs the logarithm of inhibitor concentration. Inhibitor Assay For inhibitor assays, IC50 was determined, in the presence of 1 mM NAD and 4 mM ATP (for LmNADK1) or 2 mM ATP (for SaNADK). Dixon plots were used to determine KI in the presence of 4 mM ATP (for LmNADK11) or 2 mM ATP (for Sa NADK) and three NAD concentrations (0.2, 0.5 and 1 mM). It was also checked that the inhibitors had no effect on the coupling enzyme activity. PKA assay IC50 is the inhibitor concentration which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from [gamma-32P] labeled ATP to a protein or peptide substrate. PKC assay IC50 is the inhibitor concentration which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from [gamma-32P] labeled ATP to a protein or peptide substrate. ChEMBL_98403 (CHEMBL706600) Compound was evaluated for the inhibition of Leucine aminopeptidase from porcine kidney and the inhibition constant was determined after preincubating the enzyme and inhibitor Protease Inhibition Assay The IC50 value is the inhibitor concentration that results in 50% of HIV-1 protease activity measured by a spectrophotometric assay using a chromophoric peptide. Dose-response biochemical assay of inhibitors of Rho kinase 2 (Rock2) Source (MLSCN Center Name): The Scripps Research Institute Molecular Screening Center Center Affiliation: The Scripps Research Institute, TSRI Assay Provider: Scripps Florida Network: Molecular Library Screening Center Network (MLSCN) Proposal Number: None External Assay ID: Rock2_INH_ LUMI_1536_ IC50 Name: Dose-response biochemical assay of inhibitors of Rho kinase 2 (Rock2) Description: Rho-Kinase is a serine/threonine kinase involved in the regulation of smooth muscle contraction and cytoskeletal reorganization of nonmuscle cells (1). Its inhibition is known to promote the smooth muscle relaxation. Thus, small-molecule inhibitors of Rho-Kinase may be effective probes for treatment of cerebral vasospasm (2) and potentially effective for treatment of angina (3), hypertension (4), arteriosclerosis (5), and erectile dysfunction (6). References: [1] Trauger JW, Lin FF, Turner MS, Stephens J, LoGrasso PV. Kinetic mechanism for human Rho-Kinase II (ROCK-II).Biochemistry. 2002 J ChEMBL_197028 (CHEMBL803859) Compound was evaluated for the inhibitor constant against Escherichia coli S-adenosyl-L-methionine decarboxylase ChEMBL_197029 (CHEMBL803860) compound was evaluated for the inhibitor constant against Escherichia coli S-adenosyl-L-methionine decarboxylase PKA Inhibition Assay IC50 is the inhibitor concentration, which inhibits 50% of PKA activity that catalyzes the transfer of the terminal phosphate from [gamma-32P] labeled ATP to a synthetic kemptide peptide substrate. Phosphorylase Kinasse Assay IC50 is the inhibitor concentration which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from [gamma-32P] labeled ATP to a protein or peptide substrate. Inhibitor Assay The testing for the inhibition activities of imidazole derivatives and cacodylate on gQC and sQC was evaluated at 25 C using the fluorescent substrate L-glutaminyl 2-naphthylamide (Gln-BNA). Enzyme Assay and Determination of the Inhibition Constants. Ki values were obtained from human purified enzyme. All assays were run in microtiter plates. Plates were read for 30 min at 405 nm. Rates were determined for the controls (no inhibitor) and for the inhibitors. Percent enzyme activity was determined from these rates and used in the following formula to determine Ki: Ki=(1000)(inhibitor concentration)/{[(Km + S) - (S)(ACT)]/[(ACT)(Km)] -1}, where S is the substrate concentration and ACT is the % enzyme activity for inhibitor. Enzyme Assay and Determination of the Inhibition Constants. Ki values were obtained from purified enzyme. All assays were run in microtiter plates. Plates were read for 30 min at 405 nm. Rates were determined for the controls (no inhibitor) and for the inhibitors. Percent enzyme activity was determined from these rates and used in the following formula to determine Ki: Ki=(1000)(inhibitor concentration)/{[(Km + S) - (S)(ACT)]/[(ACT)(Km)] -1}, where S is the substrate concentration and ACT is the % enzyme activity for inhibitor. Biological Activity Assay For the measurement of CDK2/cyclinE activity, enzyme (0.22 nM) was incubated with 100 mM ATP and the phosphoacceptor substrate peptide (1 mM) for one hour. For the measurement of CDK4/CyclinD activity, enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoacceptor substrate peptide (1 mM) for three hours. Potential inhibitor compounds (as HCl salts) were tested using 12-point dose response curves in single point at the Km for ATP. The IC50 of each compound was determined using GraphPad Prism. Results from the IC50 values demonstrate 200 and 100 fold selectivity for compounds Compound 1 and Compound 3 for Cdk4/CycD1 over Cdk2/CycE respectively. Competitive Displacement Binding Assay The dissociation constant of the hCA and inhibitor complex was determined by competitive displacement of a fixed concentration of dansylamide by increasing concentrations of the inhibitor using Perkin-Elmer lambda 50-B spectrofluorometer. The excitation and emission wavelengths were maintained at 330 and 448 nm. Since the binding of the inhibitor competitively displaced dansylamide from the enzyme site, the fluorescence intensity at 448 nm decreased. The dissociation constant of the enzyme-inhibitor complex was determined by monitoring the decrease in the fluorescence of the enzyme-dansylamide complex as a function of the increasing concentration of the inhibitor. Tyrosine Kinase Inhibition Assay IC50 is the inhibitor concentration which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from [gamma-32P] labeled ATP to a protein or peptide substrate. ChEMBL_35358 (CHEMBL647940) Compound was evaluated for the inhibition of Aminopeptidase M (AP-M) from porcine kidney and the inhibition constant was determined after preincubating the enzyme and inhibitor Kinase assay toxicity For nonspecific toxicity, the EC100 represents the concentration when 100% of the treated embryos exhibit either early lethality within hours of compound addition, variable embryonic defects, or developmental delay. For comparison, the effects of the known KDR inhibitor SU5416 are shown at the bottom. ChEBML_49250 Inhibition constant (KI) for the mmf chitin synthetase assay performed at constant inhibitor and varying substrate concentrations ChEMBL_4192 (CHEMBL619994) The compound was tested for inhibitory activity against 5-lipoxygenase translocation inhibitor in RBL-2H3 cells Direct Competition Assay The Ki for each inhibitor was determined by direct competition assays under steady-state conditions. The initial velocity was measured in the presence of a constant concentration of enzyme (3 nM for VIM-2 and 4 nM for VIM-24) with increasing concentrations of inhibitor (5−60 μM) against a fixed concentration (5KM) of the indicator substrate, NCF, as previously described. The reactionswere started by addition of VIM-2 or VIM-24 to substrate or to mixtures of substrate and inhibitor. ChEMBL_35364 (CHEMBL647945) Compound was evaluated for the inhibition of Aminopeptidase M (AP-M) and the inhibition constant was determined after preincubating the enzyme and inhibitor Value in the parentheses is IC50 (uM). Inhibition Activity Xanthine oxidase originated from bovine milk was incubated for 3 min with test compounds, and the initial velocity of uric acid formation was determined by adding the substrate xanthine. The initial velocity of test compound at each concentration was converted to % inhibition rate on the basis of the initial velocity under the absence of the inhibitor, thereby the inhibitor concentration needed for 50% inhibition was calculated as IC50 values. Biological Activity Kinase enzymatic reactions were performed in 384-well microplates using a 12-channel Caliper LabChip instrument as a detection device. The enzymatic phosphorylation of a peptide results in a change in net charge, enabling electrophoretic separation of product from substrate. As substrate and product are separated, two peaks of fluorescence are observed. Change in the relative fluorescence intensity of the substrate and product peaks is the parameter measured, reflecting enzyme activity. In the presence of an inhibitor, the ratio between product and substrate is altered. The signal of the product decreases, while the signal of the substrate increases.For the measurement of CDK2/cyclinE activity, enzyme (0.22 nM) was incubated with 100 mM ATP and the phosphoacceptor substrate peptide (1 mM) for one hour. For the measurement of CDK4/CyclinD activity, enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoacceptor substrate peptide (1 mM) for three hours. Potential inhibitor compounds (as HCl salts) were tested using 12-point dose response curves in single point at the Km for ATP. The IC50 of each compound was determined using GraphPad Prism. Src Inhibition Assay IC50 is the inhibitor concentration, which inhibits 50% of pp60c-src activity that catalyzes the transfer of the terminal phosphate from [gamma-32P] labeled ATP to a synthetic gastrin-based peptide substrate. LSD1 Assays Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of at least eight 3-fold serial dilutions of the respective inhibitor (e.g., from 0 to 75 μM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in duplicate. After leaving the enzyme interacting with the inhibitor, KM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 30 minutes at 37° C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 5 extra minutes at room temperature in the dark. A 1 μM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor. The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The IC50 value of each inhibitor was calculated with GraphPad Prism Software. The results presented in Table 1 below show the results of the LSD1 inhibition studies for a number of the Example compounds. In Table 2 the IC50 values for all examples tested in this assay are shown. Parnate (tranylcypromine; i.e., 2-trans phenylcyclopropylamine) was found to have a IC50 value of 35±10 micromolar. The studies show that the compounds of the invention have unexpectedly potent LSD1 inhibition. Oxadiazole SAR compounds tested by Multiplex dose response to identify specific small molecule inhibitors of Ras and Ras-related GTPases specifically Cdc42 activated mutant University of New Mexico Assay Overview: Assay Support: NIH I RO3 MH081231-01 HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases PI: Angela Wandinger-Ness, Ph.D. Co-PI: Larry Sklar, Ph.D. Assay Development: Zurab Surviladze, Ph.D. Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller Target Team Leader for the Center: Larry Sklar (lsklar@salud.unm.edu) Chemistry: University of Kansas Specialized Chemistry Center Target Team Leader for Chemistry: Jennifer Golden Dose Response Assay Background and Significance: Ras and related small molecular weight GTPases function in the regulation of signaling and cell growth, and collectively serve to control cell proliferation, differentiation and apoptosis [Tekai et al. 2001; Wennerberg et al. 2005]. The Ras-related GTPases are divided into four subfamilies with the Rab proteins regulating membrane transport, Rho proteins (including Rac and Cdc 42) regulating cytoskeletal r Formaldehyde Dehydrogenase-Coupled Demethylase (FDH) Assay For inhibition assays, powders of inhibitor compounds were dissolved in 100% (v/v) DMSO to give a 20 or 50 mM concentration and stored at -20 °C until needed. Various compounds with the concentrations ranging from 1.25 mM to 5 nM in a half-log serial dilution were pre-incubated with the reaction mixture for 15 min (0.5 mM enzyme [E], 15 mM peptide [S], 50 mM (NH4)2Fe(SO4)2, 0.1 mM αKG, and variable inhibitor [I] in the KDM5 reaction buffer with 10% DMSO). The addition of peptide and APAD+ initiated the reaction for 15 min at room temperature. Formaldehyde Dehydrogenase-Coupled Demethylase (FDH) Assay For inhibition assays, powders of inhibitor compounds were dissolved in 100% (v/v) DMSO to give a 20 or 50 mM concentration and stored at -20 °C until needed. Various compounds with the concentrations ranging from 1.25 mM to 5 nM in a half-log serial dilution were pre-incubated with the reaction mixture for 15 min (0.5 mM enzyme [E], 15 mM peptide [S], 50 mM (NH4)2Fe(SO4)2, 1 mM αKG, and variable inhibitor [I] in the KDM5 reaction buffer with 10% DMSO). The addition of peptide and APAD+ initiated the reaction for 15 min at room temperature. Biochemical Assay A generalized procedure for a standard biochemical Btk Kinase Assay that can be used to test Formula I compounds. Alternatively, the Lanthascreen assay can be used to evaluate Btk activity through quantification of its phosphorylated peptide product. The FRET (Fluorescence Resonance Energy Transfer) that occurs between the fluorescein on the peptide product and the terbium on the detection antibody decreases with the addition of inhibitors of Btk that reduce the phosphorylation of the peptide. Biological Activity Assay Kinase enzymatic reactions were performed in 384-well microplates using a 12-channel Caliper LabChip instrument as a detection device. The enzymatic phosphorylation of a peptide results in a change in net charge, enabling electrophoretic separation of product from substrate. As substrate and product are separated, two peaks of fluorescence are observed. Change in the relative fluorescence intensity of the substrate and product peaks is the parameter measured, reflecting enzyme activity. In the presence of an inhibitor, the ratio between product and substrate is altered. The signal of the product decreases, while the signal of the substrate increases.For the measurement of CDK2/cyclinE activity, enzyme (0.22 nM) was incubated with 100 mM ATP and the phosphoacceptor substrate peptide (1 mM) for one hour. For the measurement of CDK4/CyclinD activity, enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoacceptor substrate peptide (1 mM) for three hours. Potential inhibitor compounds (as HCl salts) were tested using 12-point dose response curves in single point at the Km for ATP. Kinase Enzymatic Assay Kinase enzymatic reactions were performed in 384-well microplates using a 12-channel Caliper LabChip instrument as a detection device. The enzymatic phosphorylation of a peptide results in a change in net charge, enabling electrophoretic separation of product from substrate. As substrate and product are separated, two peaks of fluorescence are observed. Change in the relative fluorescence intensity of the substrate and product peaks is the parameter measured, reflecting enzyme activity. In the presence of an inhibitor, the ratio between product and substrate is altered. The signal of the product decreases, while the signal of the substrate increases.For the measurement of CDK2/cyclinE activity, enzyme (0.22 nM) was incubated with 100 mM ATP and the phosphoacceptor substrate peptide (1 mM) for one hour. For the measurement of CDK4/CyclinD activity, enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoacceptor substrate peptide (1 mM) for three hours. Potential inhibitor compounds (as HCl salts) were tested using 12-point dose response curves in single point at the Km for ATP. ChEBML_106803 Ability to inhibit the matrix metalloprotease-2 by method of Knight et al using the fluorogenic peptide substrate. ChEBML_45241 The equilibrium dissociation constant of the inhibitor-enzyme complex of human carbonic anhydrase Dissociation Constants (KD) Measurements and Enzyme Inhibition Assay (IC50) The NMR experiments were performed to determine the binding affinity (KD) for the MMP-12 catalytic domain. The alteration of the chemical shifts induced on 2D 1H-15N HSQC upon the titration with the test compound was analyzed. The fit of the experimental data as a function of ligand concentration provided dissociation constant. The inhibition potency (IC50) was measured by fluorescent enzymatic assays. The compounds were evaluated for their ability to inhibit the hydrolysis of fluorescence-quenched peptide substrate. The enzyme was incubated with increasing concentration of inhibitor and the fluorescence (ex=328 nm; em=393 nm) was measured for 3 min after the addition of the substrate using a Varian Eclipse fluorimeter. Fitting of hydrolysis rate as a function of inhibitor concentration provided IC50. ChEMBL_4193 (CHEMBL619995) The compound was tested for inhibitory activity against 5-lipoxygenase translocation inhibitor in rat RBL-2H3 cells ChEMBL_49250 (CHEMBL660670) Inhibition constant (KI) for the mmf chitin synthetase assay performed at constant inhibitor and varying substrate concentrations ChEMBL_88707 (CHEMBL873223) The compound was tested for it's in vitro inhibitor potency against inosine monophosphate dehydrogenase II (IMPDH II) BRD4 Fluorescence Polarization (FP) The assay used a Cy5 dye-labeled BRD inhibitor PFI-411FP. The synthesis of the probe and the procedure for the assay was reported recently (Hett et al.,2015; Wu et al., 2014). Inhibition Assay The IC50 values for the PHD2 enzyme (residues 181-417) were determined by mixing increasing amounts of inhibitor with a fixed amount of enzyme (5 nM, final concentration) and Biotin labeled peptide (Biotin-Asp-Leu-Glu-Met-Leu-Ala-Pro-Tyr-Ile-Pro-Met-Asp-Asp-Asp-Phe-Gln-Leu, 1 uM final concentration) and 2-Oxyglutarate (2 uM final concentration) in 50 mM HEPES, 50 mM KCl, 0.5 mM TCEP, 2 uM FeCl2, 0.1 mg/ml BSA, at pH 7.3. The reaction was conducted by pre-incubating the enzyme in the presence of inhibitor for 60 min at room temperature. The activity of the free enzyme was measured by adding the peptide, the 2-Oxoglutarate (see above for final concentrations), and Ascorbic Acid (1 mM final concentration). The enzymatic activity was quenched after 60 min by adding an excess of a tight binding inhibitor to the assay mixture. The amount of product released was measured by using a LC/MS system (Agilent HPLC with Applied Biosystems API3000 Mass Spectrometer). Metalloenzyme Activity V79-4 cells expressing recombinant andrenodoxin and andrenodoxin reductase with either recombinant human CYP11B2 or CYP11B1 were prepared according to methods previously described (LaSala et al 2009 Anal Bioch 394:56-61). An enzyme enriched microsomal fraction was prepared from cellular lysates and subsequently used as the enzyme source for determining inhibitor IC50s. The substrate Km values were experimentally determined for 11-deoxycorticosterone (CYP11B2 substrate) and 11-deoxycortisol (CYP11B1 substrate). Enzyme assays for inhibitor screening employed CYP11B2 and CYP11B1 enzyme enriched microsomes and were run at the Km of the respective substrates. Products of the enzyme reactions, aldosterone for CYP11B2 or cortisol for CYP11B1, were measured by LC-MS. Assays were run under conditions of less than 20% substrate turnover. Inhibitor IC50s were generated by determining the product formation in the absence or presence of inhibitor at various concentrations. In the absence of the test compound, the product formed (Pt) in each data set was defined as 100% activity. In the absence of enzyme, the product formed (Pb) in each data set was defined as 0% activity. The percent activity in the presence of each inhibitor was calculated according to the following equation: % activity=(P−Pb)/(Pt−Pb), where P=the product formed in the presence of the inhibitor. The IC50 value was defined as the inhibitor concentration causing a 50% decrease in activity relative to the no inhibitor control reaction. Enzyme Assay Enzyme assays for inhibitor screening employed CYP11B2 and CYP11B1 enzyme enriched microsomes and were run at the Km of the respective substrates. Products of the enzyme reactions, aldosterone for CYP11B2 or cortisol for CYP11B1, were measured by LC-MS. Assays were run under conditions of less than 20% substrate turnover. Inhibitor IC50s were generated by determining the product formation in the absence or presence of inhibitor at various concentrations. In the absence of the test compound, the product formed (Pt) in each data set was defined as 100% activity. In the absence of enzyme, the product formed (Pb) in each data set was defined as 0% activity. Amplex Red Peroxide/Peroxidase-Coupled Assay The compounds of the invention can be tested for their ability to inhibit LSD1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc. In order to monitor LSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s) of interest, di-methylated H3-K4 peptide (Millipore) was chosen as a substrate. The demethylase activity was estimated, under aerobic conditions, by measuring the release of H2O2 produced during the catalytic process, using the Amplex Red peroxide/peroxidase-coupled assay kit (Invitrogen).Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of various concentrations of inhibitor (from 0 to 75 uM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in triplicate. ChEMBL_46665 (CHEMBL658626) Evaluated for the dissociation constant for the inhibition of caspase-3 Determination of the Inhibition Type and Constant (Ki) The Km and Kappm for the amino acid substrate were first calculated from Lineweaver-Burk plots. The Ki values were calculated from the Kappm vs [I] plot. The Ki values for the inhibitors with respect for the amino acid substrates were determined by measuring the apparent Km for the amino acid in the presence of saturating concentrations of both ATP and tRNA, and of various fixed concentrations of the inhibitor. Curve-fitting of these data using the theoretical functions for vi/v0 for various types of inhibition was made with the software Kaleidagraph (version 4.0) and was used to identify the types of inhibition and the Ki values. AdoMetDC Inhibition Assay The C-terminal his-tagged AdoMetDC was assayed by measuring the release of 14CO2 from S-adenosyl-L-[carboxy-14C]methionine (Amersham Pharmacia Biotech). For determination of the abilities of compounds to inhibit AdoMetDC, the enzyme activity was determined in the presence of no inhibitor and at least five concentrations of each potential inhibitor. The IC50 values were determined from curve fitting to plots of the inhibitor concentration versus the % inhibition of AdoMetDC. ChEMBL_45241 (CHEMBL658944) The equilibrium dissociation constant of the inhibitor-enzyme complex of human carbonic anhydrase ChEMBL_2299659 Inhibition of SRPK1 (unknown origin) using RS peptide as substrate incubated for 120 mins in the presence 33P-ATP ChEBML_160728 Tested for the inhibition of HIV-2 protease Chk1 Enzymatic Assay Chk1 kinase activity was assayed in reaction buffer containing substrate peptide, enzyme, and inhibitor in the presence of 100uM ATP/[gamma-33P] ATP. 33P incorporation was measured using a Perkin-Elmer Trilux scintillation counter. The IC50 is the inhibitor concentration, which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from 33P labeled ATP to the substrate. CA Inhibition Assay An applied photophysics stopped-flow instrument has been used for assaying the CA catalyzed CO2 hydration activity. Phenol red (at a concentration of 0.2 mM) has been used as indicator, working at the absorbance maximum of 557 nm, with 20mMHepes (pH 7.5) as buffer, and 20mM Na2SO4 (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed CO2 hydration reaction for a period of 10-100 s. The CO2 concentrations ranged from 1.7 to 17mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor at least six traces of the initial 5-10% of the reaction have been used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (0.1mM) were prepared in distilled-deionized water and dilutions up to 0.01nM were done thereafter with distilled deionized water. Inhibitor and enzyme solutions were preincubated together for 15 min to 72 h at room temperature (15 min) or 4 °C (all other incubation times) prior to assay, in order to allow for the formation of the E-I complex or for the eventual active site mediated hydrolysis of the inhibitor. Fluorescence Polarization Assay In the fluorescence polarization assay, the Bcl-XL protein is incubated with a fluorescein-tagged Bak-BH3 peptide. The Bcl-XL:Bak-BH3 peptide complex is then titrated with the test compounds, and the displacement of the Bak-BH3 peptide is measured as a function of decreasing polarized fluorescence. The fluorescence polarization values were determined using a Tecan GeniosPro plate reader using the excitation/emission wavelengths 485/535 nm. The binding affinities are reported as the inhibitory concentration of the titrant required to displace 50% of the Bak-BH3 peptide (IC50). Inhibitory Effect on HER2-Phosphorylating Activity (In Vitro) For setting the conditions for the method for measuring the in vitro inhibitory activity of a compound against HER2-phosphorylating activity, ProfilerPro Peptide 22 from PerkinElmer Inc. was used as a substrate on the basis of the report (PLoS One, 6 (7), e21487, 2011) on HER2 kinase reaction using, as a substrate, a peptide having the same sequence (5-FAM-EEPLYWSFPAKKK-CONH2) as that of ProfilerPro Peptide 22. The purified recombinant human HER2 protein used in the test was purchased from Carna Biosciences, Inc.For the inhibitory activity measurement of each compound, the synthesis example compound was first serially diluted with dimethyl sulfoxide (DMSO). Next, the HER2 protein, the substrate peptide (final concentration: 0.5 μM), manganese chloride (final concentration: 10 mM), ATP (final concentration: 6 μM), and the solution of the synthesis example compound in DMSO (final concentration of DMSO: 5%) were added into a buffer solution for kinase reaction (15 mM Tris (pH 7.5), 2 mM dithiothreitol, and 0.01% Tween 20), and the mixture was incubated at 25° C. for 40 minutes for kinase reaction. The reaction was terminated by adding EDTA (final concentration: 30 mM) thereto. Finally, the unphosphorylated substrate peptide (S) and the phosphorylated peptide (P) were separated and detected by microcapillary electrophoresis using LabChip EZ Reader II (PerkinElmer Inc.). Biochemical Assay Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of various concentrations of inhibitor (e.g., from 0 to 75 μM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in triplicate. After leaving the enzyme interacting with the inhibitor, 12.5 μM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 1 hour at 37° C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 30 extra minutes at room temperature in the dark. A 1 μM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor. Human EGFR LanthaScreen Selectivity Assay TR-FRET LanthaScreen assays were performed by incubating a dilution series of inhibitor concentrations with 20 μM ATP, 100 nM peptide substrate (FITC-C6-KKAEEEEYFELVAKK-NH2 (SEQ ID NO.: 2, American Peptide, #333778) and 600 μM of human EGFR kinase domain (Invitrogen). The assays were performed with and without pre-incubating the inhibitors with the enzyme for 60 minutes before starting the kinase reaction by adding ATP and the peptide substrate. Samples containing enzyme but no inhibitor were included to determine the maximal extent of reaction. Samples containing no enzyme served as the negative control. The kinase reaction mixtures were incubated at room temperature for 60 minutes before stopping the kinase activity by the addition of 15 mM EDTA. The extent of peptide phosphorylation by EGFR was detected using a Terbium-conjugated anti-phospho-Tyrosine antibody (Tb-PT66 antibody, invitrogen # PV3557). Phosphorylation of peptide substrate was measured by determining the ratio of 520/495 nm on an Envision Multi-label Reader (Perkin Elmer) and IC50 values were calculated by fitting the data to a four-parameter equation using XLFIt4 (IDBS). TR-FRET LanthaScreen Assay EGFR: TR-FRET LanthaScreen assays were performed by incubating a dilution series of inhibitor concentrations with 20 μM ATP, 100 nM peptide substrate (FITC-C6-KKAEEEEYFELVAKK-NH2 (SEQ ID NO.: 2, American Peptide, #333778) and 600 pM of human EGFR kinase domain (Invitrogen). The assays were performed with and without pre-incubating the inhibitors with the enzyme for 60 minutes before starting the kinase reaction by adding ATP and the peptide substrate. Samples containing enzyme but no inhibitor were included to determine the maximal extent of reaction. Samples containing no enzyme served as the negative control. The kinase reaction mixtures were incubated at room temperature for 60 minutes before stopping the kinase activity by the addition of 15 mM EDTA. The extent of peptide phosphorylation by EGFR was detected using a Terbium-conjugated anti-phospho-Tyrosine antibody (Tb-PT66 antibody, Invitrogen # PV3557). Phosphorylation of peptide substrate was measured by determining the ratio of 520/495 nm on an Envision Multi-label Reader (Perkin Elmer) and IC50 values were calculated by fitting the data to a four-parameter equation using XLFit4 (IDBS). Monoamine Oxidase Assays Briefly, a fixed amount of MAO (0.25 μg for MAO-A and 0.5 μg for MAO-B) was incubated on ice for 15 minutes in the reaction buffer, in the absence and/or in the presence of various concentrations of inhibitor (e.g., from 0 to 50 μM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. After leaving the enzyme(s) interacting with the inhibitor, 60 to 90 μM of kynuramine was added to each reaction for MAO-B and MAO-A assay respectively, and the reaction was left for 1 hour at 37° C. in the dark. The oxidative deamination of the substrate was stopped by adding 50 μL (v/v) of NaOH 2N. The conversion of kynuramine to 4-hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm, emission at 360 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure levels of fluorescence produced in the absence and/or in the presence of inhibitor. The maximum of oxidative deamination activity was obtained by measuring the amount of 4-hydroxyquinoline formed from kynuramine deamination in the absence of inhibitor and corrected for background fluorescence in the absence of MAO enzymes. Multiplex dose response to identify specific small molecule inhibitors of Ras and Ras-related GTPases specifically Cdc42 activated mutant University of New Mexico Assay Overview: Assay Support: NIH I RO3 MH081231-01 HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases PI: Angela Wandinger-Ness, Ph.D. Co-PI: Larry Sklar, Ph.D. Assay Development: Zurab Surviladze, Ph.D. Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller Target Team Leader for the Center: Larry Sklar (lsklar@salud.unm.edu) Dose Response Assay Background and Significance: Ras and related small molecular weight GTPases function in the regulation of signaling and cell growth, and collectively serve to control cell proliferation, differentiation and apoptosis [Tekai et al. 2001; Wennerberg et al. 2005]. The Ras-related GTPases are divided into four subfamilies with the Rab proteins regulating membrane transport, Rho proteins (including Rac and Cdc 42) regulating cytoskeletal rearrangements and responses to signaling, Arf/Sar proteins regulating membrane and microtubule dynamics as well Multiplex dose response to identify specific small molecule inhibitors of Ras and Ras-related GTPases specifically Rab2 wildtype University of New Mexico Assay Overview: Assay Support: NIH I RO3 MH081231-01 HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases PI: Angela Wandinger-Ness, Ph.D. Co-PI: Larry Sklar, Ph.D. Assay Development: Zurab Surviladze, Ph.D. Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller Target Team Leader for the Center: Larry Sklar (lsklar@salud.unm.edu) Dose Response Assay Background and Significance: Ras and related small molecular weight GTPases function in the regulation of signaling and cell growth, and collectively serve to control cell proliferation, differentiation and apoptosis [Takai et al. 2001; Wennerberg et al. 2005]. The Ras-related GTPases are divided into four subfamilies with the Rab proteins regulating membrane transport, Rho proteins (including Rac and Cdc 42) regulating cytoskeletal rearrangements and responses to signaling, Arf/Sar proteins regulating membrane and microtubule dynamics as well Multiplex dose response to identify specific small molecule inhibitors of Ras and Ras-related GTPases specifically Rac activated mutant University of New Mexico Assay Overview: Assay Support: NIH I RO3 MH081231-01 HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases PI: Angela Wandinger-Ness, Ph.D. Co-PI: Larry Sklar, Ph.D. Assay Development: Zurab Surviladze, Ph.D. Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller Target Team Leader for the Center: Larry Sklar (lsklar@salud.unm.edu) Dose Response Assay Background and Significance: Ras and related small molecular weight GTPases function in the regulation of signaling and cell growth, and collectively serve to control cell proliferation, differentiation and apoptosis [Takai et al. 2001; Wennerberg et al. 2005]. The Ras-related GTPases are divided into four subfamilies with the Rab proteins regulating membrane transport, Rho proteins (including Rac and Cdc 42) regulating cytoskeletal rearrangements and responses to signaling, Arf/Sar proteins regulating membrane and microtubule dynamics as well Multiplexed dose response to identify specific small molecule inhibitors of Ras and Ras-related GTPases specifically Rac wildtype University of New Mexico Assay Overview: Assay Support: NIH I RO3 MH081231-01 HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases PI: Angela Wandinger-Ness, Ph.D. Co-PI: Larry Sklar, Ph.D. Assay Development: Zurab Surviladze, Ph.D. Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller Target Team Leader for the Center: Larry Sklar (lsklar@salud.unm.edu) Dose Response Assay Background and Significance: Ras and related small molecular weight GTPases function in the regulation of signaling and cell growth, and collectively serve to control cell proliferation, differentiation and apoptosis [Takai et al. 2001; Wennerberg et al. 2005]. The Ras-related GTPases are divided into four subfamilies with the Rab proteins regulating membrane transport, Rho proteins (including Rac and Cdc 42) regulating cytoskeletal rearrangements and responses to signaling, Arf/Sar proteins regulating membrane and microtubule dynamics as well Multiplexed dose response to identify specific small molecule inhibitors of Ras and Ras-related GTPases specifically Ras wildtype University of New Mexico Assay Overview: Assay Support: NIH I RO3 MH081231-01 HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases PI: Angela Wandinger-Ness, Ph.D. Co-PI: Larry Sklar, Ph.D. Assay Development: Zurab Surviladze, Ph.D. Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller Target Team Leader for the Center: Larry Sklar (lsklar@salud.unm.edu) Dose Response Assay Background and Significance: Ras and related small molecular weight GTPases function in the regulation of signaling and cell growth, and collectively serve to control cell proliferation, differentiation and apoptosis [Tekai et al. 2001; Wennerberg et al. 2005]. The Ras-related GTPases are divided into four subfamilies with the Rab proteins regulating membrane transport, Rho proteins (including Rac and Cdc 42) regulating cytoskeletal rearrangements and responses to signaling, Arf/Sar proteins regulating membrane and microtubule dynamics as well Competitive Inhibition Assay Analysis of the inhibition activation of flNS3 by the inhibitors was performed with the standard assay, allowing the inhibitor to preincubate with NS3 and NS4 for 15 min. prior to addition of substrate. CA Inhibition Assay An Applied Photophysics stopped-flow instrument has been used for assaying the CA catalysed CO2 hydration activity. Phenol red (at a concentration of 0.2 mM) has been used as an indicator, working at the absorbance maximum of 557 nm, with 20 mM Hepes (pH 7.5) as buffer, and 20 mM Na2SO4 (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed CO2 hydration reaction for a period of 10-100 s. The CO2 concentrations ranged from 1.7 to 17 mM for thedetermination of the kinetic parameters and inhibition constants19. For each inhibitor at least six traces of the initial 5-10% of the reaction have been used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (0.1 mM) were prepared in distilled-deionized water and dilutionsup to 0.01 nM were done thereafter with distilled deionized water. Inhibitor and enzyme solutions were preincubated together for 15 min-72 h at room temperature(15 min) or 4 °C (all other incubation times) prior to assay, in order to allow for the formation of the E-I complex or for the eventual active site mediated hydrolysis of the inhibitor. ChEMBL_38359 (CHEMBL651291) In vitro inhibitory activity against Bak-Bh3 peptide binding to the Bcl-2 IMAP Assay Cdk9/cyclinT1 is purchased from Millipore, cat #14-685. The final total protein concentration in the assay 4 nM. The 5TAMRA-cdk7tide peptide substrate, 5TAMRA-YSPTSPSYSPTSPSYSTPSPS--COOH, is purchased from Molecular Devices, cat#R7352. The final concentration of peptide substrate is 100 nM. The ATP substrate (Adenosine-5'-triphosphate) is purchased from Roche Diagnostics, cat#1140965. The final concentration of ATP substrate is 6 uM. IMAP (Immobilized Metal Assay for Phosphochemicals) Progressive Binding reagent is purchased from Molecular Devices, cat#R8139. Fluorescence polarization (FP) is used for detection. The 5TAMRA-cdk7tide peptide is phosphorylated by Cdk9/cyclinT1 kinase using the ATP substrate. The Phospho-5TAMRA-cdk7tide peptide substrate is bound to the IMAP Progressive Binding Reagent. Kinetics Assay for IC50 Determination IC50 determinations for cSrc kinases were measured with the HTRF KinEASE-TK assay from Cisbio according to the manufacturer instructions. A biotinylated poly-Glu-Tyr substrate peptide was phosphorylated by cSrc. After completion of the reaction, an anti-phosphotyrosine antibody labeled with europium cryptate and streptavidin labeled with the fluorophore XL665 were added. The FRET between europium cryptate and XL665 was measured to quantify the phosphorylation of the substrate peptide. Kinase, substrate peptide, and inhibitor were preincubated for 2 h before the reaction was started by addition of ATP. A Tecan Safire2 plate reader was used to measure the fluorescence of the samples at 620 nm (Eu-labeled antibody) and 665 nm (XL665 labeled streptavidin) 60 us after excitation at 317 nm. The quotient of both intensities for reactions made with eight different inhibitor concentrations was fit to a Hill four-parameter equation to determine IC50 values. Each reaction was performed in duplicate, and at least three independent determinations of each IC50 were made. Fluorescence Resonance Energy Transfer Assay (FRET) The enzymatic reaction started by the addition fluorogenic peptide substrate, MAPKKide to the buffer containing LF and inhibitor compound. Cleavage of the substrate by LF released the fluorophore and full fluorescence was restored. Fluorescence intensity (Ex: 320 nm, Em: 420 nm) was monitored for 15 min at room temperature and the Ki values were calculated using the program BatchKi (BioKin Ltd., Pullman, WA). ChEBML_1703652 Inhibition of Rho-associated protein kinase 1 (unknown origin) ChEMBL_2274001 Inhibition of human USP7 using Ub-Rho as substrate ChEMBL_2213969 (CHEMBL5127101) Inhibition of UCHL1 (unknown origin) using Ub-Rho as substrate preincubated for 30 mins followed by substrate addition ChEMBL_1875746 (CHEMBL4377140) Inhibition of human PNP assessed as inhibitor constant for enzyme-inhibitor complex formation LSD1 Assay The compounds of the invention can be tested for their ability to inhibit LSD1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc. In order to monitor LSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s) of interest, di-methylated H3-K4 peptide (Millipore) was chosen as a substrate. The demethylase activity was estimated, under aerobic conditions, by measuring the release of H2O2 produced during the catalytic process, using the Amplex Red peroxide/peroxidase-coupled assay kit (Invitrogen).Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of various concentrations of inhibitor (e.g., from 0 to 75 μM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in triplicate. After leaving the enzyme interacting with the inhibitor, 12.5 μM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 1 hour at 37° C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 30 extra minutes at room temperature in the dark. A 1 μM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor.The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The Ki (IC50) of each inhibitor was estimated at half of the maximum activity. Enzymatic Assay Methods: A peptide mobility shift assay was used to quantify the phosphorylation of the JAKtide (JAK-2 and JAK-3) or the IRS-1 peptide (JAK-1 and Tyk-2). Reactions were carried out in a 384-well plate (Matrical MP-101) in a 10 microliter total volume. Reaction mixtures contained 20 mM HEPES, pH 7.4, 10 mM magnesium chloride, 0.01% bovine serum albumin (BSA), 0.0005% Tween-20, ATP (4 micromolar for JAK-2 and JAK-3, 40 micromolar for JAK-1 and 7 micromolar for Tyk-2)), 2% DMSO and 1 micromolar peptide substrate (JAKtide for JAK-2 and JAK-3 or IRS-1 peptide for JAK-1 and Tyk-2). Compounds were diluted serially in 100% dimethyl sulfoxide and tested in an 11 point dose response in duplicate or quadruplicate (200 nl of compound/DMSO was added per 10 microliter reaction). The reactions were initiated by the addition of enzyme to the final concentration of 2 nM JAK-2, 1 nM JAK-3, 7 nM Tyk2 or 20 nM JAK-1. The assay was run for 240 minutes for JAK-1, 150 minutes for JAK-2, 90 minutes for JAK-3. Inhibition of Cellular Release of Amyloid Peptide 1-40 Chinese hamster ovary cells are transfected with the human gene for amyloid precursor protein. The cells are plated at a density of 8000 cells/well into 96-well microtiter plates and cultivated for 24 hours in DMEM cell culture medium containing 10% FCS. The test compound is added to the cells at various concentrations, and the cells are cultivated for 24 hours in the presence of the test compound. The supernatants are collected, and the concentration of amyloid peptide 1-40 is determined using state of the art immunoassay techniques, for example sandwich ELISA, homogenous time-resolved fluorescence (HTRF) immunoassay, or electro-chemiluminescence immunoassay. The potency of the compound is calculated from the percentage of inhibition of amyloid peptide release as a function of the test compound concentration. ChEMBL_45240 (CHEMBL658943) The equilibrium dissociation constant of the inhibitor-enzyme complex of human Carbonic anhydrase II Spectrophotometric Assay Enzyme activities were measured in the presence of the test inhibitor in spectrophotometric assay. In Vitro Kinase Inhibition Assay IC50 is the inhibitor concentration, which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from radiolabeled ATP to the peptide substrate. Use of radiolabeled ATP allows this transfer to be monitored by scintillation counting. Biological Assays-Inhibition of LSD1 Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of at least eight 3-fold serial dilutions of the respective inhibitor (e.g., from 0 to 75 μM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in duplicate. After leaving the enzyme interacting with the inhibitor, KM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 30 minutes at 37° C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 5 extra minutes at room temperature in the dark. A 1 μM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor.The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The IC50 value of each inhibitor was calculated with GraphPad Prism Software. LSD1 Assay Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of various concentrations of inhibitor (e.g., from 0 to 75 μM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in triplicate. After leaving the enzyme interacting with the inhibitor, 12.5 μM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 1 hour at 37° C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 30 extra minutes at room temperature in the dark. A 1 μM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Luminescent Kinase Assay Inhibition of TgCDPK1 and CpCDPK1 was determined using a luminescent kinase assay which measures ATP depletion in the presence of the Syntide 2 peptide substrate (KinaseGlo. Notably, both kinases were tested at the same ATP concentration which allows direct comparison of inhibitor potencies due to these enzymes possessing similar Kms for this cofactor. ChEBML_4308 Measuring the affinity of leukotriene synthesis inhibitor for 5-Lipoxygenase activating protein (FLAP) by using [125I]L-691831 as radioligand. ChEMBL_4309 (CHEMBL618417) Measuring the affinity of leukotriene synthesis inhibitor for 5-lipoxygenase activating protein by using [125I]L-691831 as radioligand. In Vitro Inhibitory Activity Assay For the inhibitory activity measurement of each compound, the compound of the present invention or staurosporine was first serially diluted with dimethyl sulfoxide (DMSO). Next, the HER2 protein, the substrate peptide (final concentration: 0.5 uM), manganese chloride (final concentration: 10 mM), ATP (final concentration: 6 uM), and the solution of the compound of the present invention in DMSO (final concentration of DMSO: 5%) were added into a buffer solution for kinase reaction (15 mM Tris (pH 7.5), 2 mM dithiothreitol, and 0.01% Tween 20), and the mixture was incubated at 25° C. for 40 minutes for kinase reaction. The reaction was terminated by adding EDTA (final concentration: 30 mM) thereto. Finally, the unphosphorylated substrate peptide (S) and the phosphorylated peptide (P) were separated and detected by microcapillary electrophoresis using LabChip EZ Reader II (PerkinElmer Inc.). SARS-CoV 3CL Protease Inhibition Assay The effects of compound on enzyme activity were measured by using a fluorogenic peptide cleavage assay. Enhanced fluorescence caused by cleavage of the substrate peptide was monitored at 538 nm with excitation at 355 nm. The initial velocities of the inhibited reactions of 50 nM SARS 3CL protease and 6 uM fluorogenic substrate were plotted against the different inhibitor concentrations to obtain the IC50. Inhibitor Screening Assay The inhibitor screening assays were performed in 96-well format with 1152 small molecules found in the Prestwick chemical library (Prestwick Chemical, France). Malachite Green Assay A colorimetric assay for the release of inorganic phosphate upon hydrolysis of ATP was used to determine the potency of Hsp 90 inhibitor against enzyme. ChEMBL_160728 (CHEMBL873426) Tested for the inhibition of HIV-2 protease Src IC50 Determination IC50 values were determined with the Z lyte assay system (Invitrogen). The reactions were performed in 384-well small volume plates from Greiner (#784076). The kinase reaction for cSrc consisted of kinase buffer, kinase, peptide and ATP. For each IC50 determination, 16 different concentrations of inhibitor (range from 250,000 to 10 nM) were used in triplicate and at least three independent experiments were performed. Before starting the kinase reaction, enzyme and inhibitor were incubated for 40 min. Following the kinase reaction, Development Solution (included with the kit) was added to cleave the remaining unphosphorylated peptide. Following a 1 h incubation time with Development Solution, Stop Solution (included with the kit) was added to the reaction mixture. Fluorescence was then measured with a Spectramax M5 plate reader from Molecular Devices or a Safire2 from Tecan. Upon excitation of coumarin at 400 nm, fluorescence emission was measured at 445 nm (coumarin) and 520 nm (fluorescein). The ratio of coumarin to fluorescein emission was used to calculate the percentage of phosphorylation of the peptide by the kinase. TACE Inhibition Assay The compounds were tested for TACE inhibition using fluorescence resonance energy transfer (FRET) assay. TACE catalyzed cleavage of the substrate peptide liberates the fluoropore from the proximity of the adjacent quenching moiety, and an increase in fluorescence signal results. HER2-Phosphorylating Activity For setting the conditions for the method for measuring the in vitro inhibitory activity of a compound against HER2-phosphorylating activity, ProfilerPro Peptide 22 from PerkinElmer Inc. was used as a substrate on the basis of the report (PLoS One, 6 (7), e21487, 2011) on HER2 kinase reaction using, as a substrate, a peptide having the same sequence (5-FAM-EEPLYWSFPAKKK-CONH2) as that of ProfilerPro Peptide 22. The purified recombinant human HER2 protein used in the test was purchased from Carna Biosciences, Inc. Also, staurosporine (Eur. J. Biochem., 234, p. 317-322, 1995; and Nat. Biotechnol., 26 (1), p. 127-132, 2008), which is a multikinase inhibitor having Her2 inhibitory activity, was purchased from Enzo Life Sciences, Inc. (item No.: ALX-380-014) and used as a positive control in this test.For the inhibitory activity measurement of each compound, the compound of the present invention or staurosporine was first serially diluted with dimethyl sulfoxide (DMSO). Next, the HER2 protein, the substrate peptide (final concentration: 0.5 uM), manganese chloride (final concentration: 10 mM), ATP (final concentration: 6 uM), and the solution of the compound of the present invention in DMSO (final concentration of DMSO: 5%) were added into a buffer solution for kinase reaction (15 mM Tris (pH 7.5), 2 mM dithiothreitol, and 0.01% Tween 20), and the mixture was incubated at 25° C. for 40 minutes for kinase reaction. The reaction was terminated by adding EDTA (final concentration: 30 mM) thereto. Finally, the unphosphorylated substrate peptide (S) and the phosphorylated peptide (P) were separated and detected by microcapillary electrophoresis using LabChip EZ Reader II (PerkinElmer Inc.). The amount of phosphorylation reaction was determined from the respective peak heights of S and P. The compound concentration which can suppress the phosphorylation reaction by 50% was defined as an IC50 value (nM). ULK1 inhibition assay ULK1 inhibition assay is a screening assay to identify compounds that inhibit kinase activity of ULK1 using the ULKtide peptide. In some embodiments, the method contacting a candidate compound, ULK1 and a recombinant ULKtide peptide (or variant thereof); detecting phosphorylation of the recombinant peptide in the presence and absence of the candidate compound; and identifying a compound that inhibits kinase activity of ULK1 if phosphorylation of the recombinant peptide is decreased in the presence of the candidate compound compared to in the absence of the candidate compound. CA Inhibition Assay An Applied Photophysics stopped-flow instrument has been used for assaying the CA catalyzed CO2 hydration activity [Khalifah et al., J. Biol. Chem., 246:2561-73]. Phenol red (at a concentration of 0.2 mM) has been used as an indicator, working at the absorbance maximum of 557 nm, with 20 mM Hepes (pH 7.4 for hCA I and II) or with 20 mM Tris (pH 8.4, for ScCA) as buffers, and 20 mM NaClO4 (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed CO2 hydration reaction for a period of 10-100 s. The CO2 concentrations ranged from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor at least six traces of the initial 5%-10% of the reaction have been used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (10 mM) were prepared in distilled-deionized water and dilutions up to 0.001 nM were done thereafter with the assay buffers. Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of the E-I complex. The concentration of the enzymes in the assays was of 8.0 nM for hCA I, of 5.9nM for hCA II and of 12.5 nM for ScCA, respectively. Biological Assay The compounds of the invention can be tested for their ability to inhibit LSD1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc (catalog reference number 50100: human recombinant LSD1, GenBank accession no. NM_015013, amino acids 158-end with N-terminal GST tag, MW: 103 kDa). In order to monitor LSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s) of interest, di-methylated H3-K4 peptide (Anaspec) was chosen as a substrate. The demethylase activity was estimated, under aerobic conditions, by measuring the release of H2O2 produced during the catalytic process, using the Amplex Red hydrogen peroxide/peroxidase assay kit (Invitrogen).Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of at least eight 3-fold serial dilutions of the respective inhibitor (e.g., from 0 to 75 uM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in duplicate. After leaving the enzyme interacting with the inhibitor, KM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 30 minutes at 37° C. in the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 5 extra minutes at room temperature in the dark. A 1 uM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor. The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The IC50 value of each inhibitor was calculated with GraphPad Prism Software. Enzymatic Assay A peptide mobility shift assay was used to quantify the phosphorylation of the JAKtide (JAK2 and JAK3) or the IRS-1 peptide (JAK1 and Tyk2). Reactions were carried out in a 384-well plate (Matrical MP-101) in a 10 L total volume. Reaction mixtures contained 20 mM HEPES, pH 7.4, 10 mM magnesium chloride, 0.01% bovine serum albumin (BSA), 0.0005% Tween-20, ATP (4 M for JAK2 and JAK3, 40 M for JAK1 and 7 M for Tyk2)), 2% DMSO and 1 M peptide substrate (JAKtide for JAK2 and JAK3 and IRS-1 peptide for JAK1 and Tyk2). Compounds were diluted serially in 100% dimethyl sulfoxide and tested in an 11 point dose response in duplicate or quadruplicate (200 nl of compound/DMSO was added per 10 L reaction). The reactions were initiated by the addition of enzyme to the final concentration of 2 nM JAK2, 1 nM JAK3, 12 nM Tyk2 or 20 nM JAK1. The assay was run for 240 minutes for JAK1, 150 minutes for JAK2, 90 minutes for JAK3 and 70 minutes for Tyk2. ChEMBL_1875747 (CHEMBL4377141) Inhibition of human PNP assessed as inhibitor constant for enzyme-inhibitor-substrate complex formation Kinase Inhibition Assay For kinase inhibition assays, the final concentrations of the enzymes were 15, 14.5, 14.5, and 8.8 nM for CLK1, CLK2, CLK3, and Dyrk1A (Invitrogen, catalog no. PV3785), respectively. The compound concentrations ranged from 15503 to 121 nM and from 1550 to 12 nM. The RS domainderived peptide (GRSRSRSRSR) (Anaspec, catalog no. 61722) for CLK1 and CLK3, Dyrktide (RRRFRPASPLRGPPK) (Anaspec, catalog no. 62698) for Dyrk1A, and S6K peptide for CLK2 were used as substrates at a concentration of 5 μM. ChEBML_73023 Tested for the inhibition against the human dihydrofolate reductase Protease Inhibition Assay All enzyme assays were performed under initial velocity and steady-state conditions. The conditions for the enzyme catalyzed hydrolysis of the cleavage site peptide VSQN-(beta-naphthylalanine)-PIV were established with respect to time and enzyme concentration to yield linear initial velocity data. IC50 is inhibitor concentration, which inhibits 50% peptide cleavage activity of HIV protease. The detection of product was monitored with fluorescence (excitation 270 nm, emission 330 nm). In vitro binding of inhibitor to hCA-II Inhibitor binding to CA II was determined using a fluorescence competition assay. Displacement of dansylamide and binding of the inhibitor was determined by measuring and comparing the average fluorescence intensities of the treated versus control reactions. Binding constants were estimated from a Dixon plot of the data (reciprocal of the average fluorescence intensity versus inhibitor concentration) Shift AlphaScreen Assay The AlphaScreen Assay is modified to include the testing of inhibitors against ADAMTS-5 in the presence of 50% Lewis rat plasma in order to determine the effects of plasma protein binding on inhibitor potency. The ratio between the IC50 of the inhibitor against ADAMTS-5 in 50% Lewis rat plasma versus the IC50 of the inhibitor in buffer is calculated and is described as the plasma shift of the inhibitor. The assay is completed in the same manner using 10 nM ADAMTS-5 instead of 2.1 nM. A similar assay is used with dog ADAMTS-4 in the presence of 25% dog plasma. JAK Enzymatic Assay Methods: A peptide mobility shift assay was used to quantify the phosphorylation of the JAKtide (JAK-2 and JAK-3) or the IRS-1 peptide (JAK-1 and Tyk-2). Reactions were carried out in a 384-well plate (Matrical MP-101) in a 10 microliter total volume. Reaction mixtures contained 20 mM HEPES, pH 7.4, 10 mM magnesium chloride, 0.01% bovine serum albumin (BSA), 0.0005% Tween-20, ATP (4 micromolar for JAK-2 and JAK-3, 40 micromolar for JAK-1 and 7 micromolar for Tyk-2)), 2% DMSO and 1 micromolar peptide substrate (JAKtide for JAK-2 and JAK-3 or IRS-1 peptide for JAK-1 and Tyk-2). Compounds were diluted serially in 100% dimethyl sulfoxide and tested in an 11 point dose response in duplicate or quadruplicate (200 nl of compound/DMSO was added per 10 microliter reaction). The reactions were initiated by the addition of enzyme to the final concentration of 2 nM JAK-2, 1 nM JAK-3, 7 nM Tyk2 or 20 nM JAK-1. The assay was run for 240 minutes for JAK-1, 150 minutes for JAK-2, 90 minutes for JAK-3 and 60 minutes for Tyk-2. KDR Kinase Inhibition Assay Conditions for assaying the in vitro inhibitory activity of the compound against KDR kinase activity were set with reference to the statement in the LabChip.TM. series reagent supplies price list of Caliper Life Sciences, Inc. that FL-Peptide 22 is adaptable as a substrate peptide to KDR kinase activity assay. The purified recombinant human KDR protein used in the test is a house purified product. For the inhibitory activity assay on the compound, the compound of the present invention was first serially diluted with dimethyl sulfoxide (DMSO). Next, the purified human KDR protein FL-Peptide 22 (final concentration: 1.5 uM), magnesium chloride (final concentration: 10 mM), ATP (final concentration: 200 uM), and each DMSO solution of the compound of the present invention (final concentration of DMSO: 5%) were added into a buffer solution for reaction (100 mM HEPES pH 7.5, 1 mM DTT, 0.003% Brij 35, 0.04% Tween-20, 0.05% CHAPSO) supplemented with a phosphatase inhibitor cocktail. Fluorescence Polarization Assay Assays effective in monitoring the inhibition of the MLL binding to menin were developed during experiments performed during the development of embodiments of the present invention. A fluorescein-labeled 12-amino acid peptide derived from MLL containing the high affinity menin binding motif was produced (Yokoyama et al., Cell., 2005. 123(2): p. 207-18., herein incorporated by reference in its entirety). Upon binding of the peptide (1.7 kDa) to the much larger menin (-67 kDa), the rotational correlation time of the fluorophore (peptide labeled with fluorescein at N-terminus) changes significantly, resulting in a substantial increase in the measured fluorescence polarization and fluorescence anisotropy (excitation at 500 nm, emission at 525 nm). The fluorescence polarization (FP) assay was utilized to determine the Kd for the binding of menin and the MLL peptide using a serial dilution of menin and 50 nM fluorescein-labeled MLL peptide. Inhibition Assay The assay was monitored spectrophotometrically through the consumption of beta-NADPH. The inhibitor assays contained inhibitor at concentrations of 0.1-15 mM cyclic analogues and 5-35 mM phosphonic acid derivates. Mobility Shift Assay (MSA) Type B The active BTK assay consisted of phosphorylated form of full length BTK. The assay was performed in a buffer solution utilized in the inactive BTK assay. The enzyme inhibitor complexes was incubated for 30 minutes at the room temperature and the kinase activation reaction was initiated by the addition of 1 μM Srctide peptide substrate and 16M ATP. After incubation at room temperature for 60 minutes, the reaction was stopped and the mobility shift was measured as described above for the inactive BTK assay. The data of inactive and active BTK assays was fit to a 4 parameter logistic model to calculate the IC50 value. Inhibitor Assay The assay mixture (100 L) containing 50 mM MOPS (pH 6.5), 2 mM pNPP and PTP1B were monitored at 405 nm for 2 min at 30 C. CA Inhibition Assay An Applied Photophysics stopped-flow instrument has been used for assaying the CA catalysed CO2 hydration activity [Khalifah et al., J. Biol. Chem., 246:2561-2573]. Phenol red (at a concentration of 0.2 mM) has been used as indicator, working at the absorbance maximum of 557 nm, with 20 mM Hepes (pH 7.5) as buffer, and 20 mM Na2SO4 (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed CO2 hydration reaction for a period of 10-100 s. The CO2 concentrations ranged from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor, at least six traces of the initial 5-10% of the reaction have been used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (0.1 mM) were prepared in distilled-deionized water and dilutions up to0.01 nM were done thereafter with distilled-deionized water. Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of the E-I complex. CA Inhibition Assay An Applied Photophysics stopped-flow instrument has been used for assaying the CA catalysed CO2 hydration activity [Khalifah et al., J. Biol. Chem., 246:2561-2573]. Phenol red (at a concentration of 0.2 mM) has been used as indicator, working at the absorbance maximum of 557 nm, with 10-20 mM Hepes (pH 7.5, for α-CAs) or TRIS (pH 8.3 for β-CAs) as buffers, and 20 mM Na2SO4 (for α-CAs) or 20 mM NaCl− for β-CAs (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed CO2 hydration reaction for a period of 10-100 s. The CO2 concentrations ranged from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor, at least six traces of the initial 5-10% of the reaction have been used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (10 mM) were prepared in distilled-deionized water and dilutions up to 0.01 nM were done thereafter with distilled-deionized water. Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of the E-I complex. The inhibition constants were obtained by nonlinear least-square methods using PRISM 3, whereas the kinetic parameters for the uninhibited enzymes from Lineweaver-Burk plots, as reported earlier. CA Inhibition Assay An Applied Photophysics stopped-flow instrument has been used for assaying the CA-catalyzed CO2 hydration activity [Khalifah et al., J. Biol. Chem., 246:2561-2573]. Phenol red (at a concentration of 0.2 mM)has been used as indicator, working at the absorbance maximum of 557 nm with 10-20 mM Hepes (pH 7.5, for α-CAs) or TRIS (pH 8.3 for β-CAs) as buffers, and20 mM Na2SO4 (for α-CAs) or 20 mM NaCl for β-CAs (for maintaining constant the ionic strength), following the initial rates of the CA-catalyzed CO2 hydration reaction for a period of 10-100 s. The CO2 concentrations ranged from 1.7 to 17 mM for the determination of the kinetic parameters and inhibition constants. For each inhibitor, at least six traces of the initial 5-10% of the reaction have been used for determining the initial velocity. The uncatalyzed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (10 mM) were prepared in distilled deionized water and dilutions up to 0.01 nM were done thereafter with distilled-deionized water. Inhibitor andenzyme solutions were preincubated together for 15 min at room temperature prior to assay in order to allow for the formation of the E-I complex. The inhibition constants were obtained by non-linear least-squares methods using PRISM 3, whereas the kinetic parameters for the uninhibited enzymes from Lineweaver-Burk plots,as reported earlier. ChEMBL_46814 (CHEMBL657058) The compound was tested for Ki value against rat whole brain P2 membrane preparation in absence of enzyme inhibitor PMSF ChEMBL_46816 (CHEMBL657060) The compound was tested for Ki value against rat whole brain P2 membrane preparation in presence of enzyme inhibitor PMSF. Kinase Assay Activated Akt isoforms and pleckstrin homology domain deletion constructs were assayed utilizing a GSK-derived biotinylated peptide substrate. The extend of peptide was determined by Homogeneous Time Resolved Fluorescence (HTRF) using a lanthanide chelate (Lance)-coupled monoclonal antibody specific for the phosphopeptide in combination with a streptavidin-linked allophycocyanin (SA-APC) fluorophore which will bind to the biotin moiety on the peptide. SARS-CoV 3CL Protease Inhibition Assay The effects of compound on enzyme activity were measured by using a fluorogenic peptide cleavage assay. Enhanced fluorescence caused by cleavage of the substrate peptide was monitored at 538 nm with excitation at 355 nm. The Ki measurements were performed at two fixed inhibitor concentrations and various substrate concentrations. Antimalarial Testing In Vitro (IC50) and Measurement of Inhibition Constant (Ki) The concentration of inhibitor that inhibited 50% of the parasite growth (IC50) was determined from the sigmoidal curve obtained by plotting the percentages of [3H]-hypoxanthine incorporation against drug concentrations. The activity of pfDHFR-TS was determined spectrophotometrically using a UV-Vis spectrophotometer. The Ki values of the inhibitors for the wild-type and mutant enzymes were determined by fitting to the equation IC50 = Ki(1 + ([S]/Km)), where IC50 is the concentration of inhibitor that inhibits 50% of the enzyme activity under the standard assay condition and Km is the Michaelis constant for the substrate H2folate. Kinase Inhibition Assay Enzymatic reactions were initiated by adding kinase to the reaction mixture containing ATP, [gamma-33P] ATP, peptide substrate and test inhibitor compound. The reactions were terminated after 10 min at 23 °C. The reaction mix was then transferred to filter plates for scintillation counting. Each inhibitor compound was added to the reaction to produce an 11-point dose-response curve (0.0001 to 10 uM). The IC50 values were estimated from data fit to the equation: y =Vmax X (1 - (x/(K + x)). ChEMBL_143851 (CHEMBL747208) The compound was tested for the binding affinity against Neuropeptide Y receptor type 2 In Vitro Enzyme Assay The proteolytic cleavage of N-acyl aminocoumarins by cathepsins was conducted in Dynatech Microfluor fluorescence 96-well microtiter plates, and readings were taken on a Molecular Devices Spectra Max Gemini XS instrument. The excitation wavelength was 355 nm and the emission wavelength was 450 nm for peptidyl-AMC substrates. Generation of AMC was monitored over 5 min. The dissociation constants (Ki) were determined from the IC50 values taken from plots of Vi/Vo versus inhibitor concentration, where Vo is the velocity in the absence of the inhibitor and Vi is the velocity with the inhibitor. The IC50 values were converted to Ki by the equation Ki = IC50 - Et/2, where Et is the enzyme concentration. ChEBML_60356 The compound was evaluated for the dissociation constant for inhibiting the binding of [3H]-SCH- 23390 at Dopamine receptor D1 ChEBML_164495 Inhibitory activity against peptide binding to the RRE RNA was determined ChEBML_34991 Displacement of [125I]- ANP from the Atrial Natriuretic Peptide Clearance Receptor. ChEBML_34995 Displacement of [125I]- ANP from the Atrial natriuretic peptide receptor A. ChEMBL_154313 (CHEMBL762798) Inhibition of the isolated native E. coli peptide deformylase (PDF) Profiling Assay to determine GST-GSH interactions in multiplex bead-based assays University of New Mexico Assay Overview: Assay Support: NIH I RO3 MH081231-01 HTS to identify specific small molecule inhibitors of Ras and Ras-related GTPases PI: Angela Wandinger-Ness, Ph.D. Co-PI: Larry Sklar, Ph.D. Assay Development: Zurab Surviladze, Ph.D. Assay Implementation: Zurab Surviladze, Danuta Wlodek, Terry Foutz, Mark Carter, Anna Waller Profiling Assay Background and Significance: The objective of the HTS associated with this counterscreen was to identify small molecule regulators of Ras and Ras-related GTPases (see Summary Report and PubChem AIDs 1333, 1334, 1335, 1336, 1337, 1339, 1340, 1341). The primary HTS assay was a no-wash fluorescent GTP-binding assay adapted to multiplexed, high-throughput measurements whereby multiple GTPases were simultaneously screened against the MLSCN library. The specificity is based on the observation that individual GTPases including wt and activated forms exhibit measurably distinct affinities for Bodipy-FI-GTP vs GTP. The assay DHODH Inhibition Assay The assays were carried out by using a colorimetric DCIP method, which uses the colorimetric reagent 2, 6-dichlorophenolindophenol as the final electron acceptor. DCIP reduction is stoichiometrically equivalent to oxidation of dihydroorotate. Changes in absorbance were quantified on a plate reader and data were analyzed to measure the reduction of DCIP as a decrease in absorbance at 600 nm. For the determination of the IC50 values (concentration of inhibitor required for 50% inhibition) different inhibitor concentrations were applied. BTK Inhibitory Activity With regard to the setting of the conditions for a method for measuring the inhibitory activity of a compound against BTK kinase activity in vitro, it is described in the consumable reagent supplies price list for LabChip (registered trademark) series of PerkinElmer, Inc. that FL-PEPTIDE 2 corresponds to a substrate peptide for the measurement of BTK kinase activity. Therefore, FL-PEPTIDE 2 was used as a substrate. The purified recombinant human BTK protein used in the test was purchased from Carna Biosciences, Inc.With regard to the measurement of the inhibitory activity of the compounds, firstly, the compounds of the present invention were diluted stepwise with dimethyl sulfoxide (DMSO). Subsequently, BTK protein, a substrate peptide (final concentration was 1 μM), magnesium chloride (final concentration was 10 mM), ATP (final concentration was 45 μM), and a DMSO solution of the compounds of the present invention (final concentration of DMSO was 5%) were added to a buffer solution for kinase reaction (20 mM HEPES (pH 7.5), 2 mM dithiotheitol, 0.01% Triton X-100), and after the solution was incubated for 40 minutes at 25° C., a kinase reaction was carried out. The reaction was terminated by adding EDTA thereto in order to obtain a final concentration of 30 mM. Finally, a substrate peptide that was not phosphorylated (S) and a phosphorylated peptide (P) were separated and detected by microchannel capillary electrophoresis using a LabChip EZ Reader II (PerkinElmer, Inc.). The amounts of phosphorylation reaction were determined from the respective peak heights of S and P, and the compound concentration at which the phosphorylation reaction could be suppressed in 50% was defined as the IC50 value (nM). Immunofluorescence Resonance Energy Transfer (FRET) Assay The FRET assay was performed essentially as described in Gruninger-Leitch et al., Journal of Biological Chemistry (2002) 277(7) 4687-93 (Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases). In summary, a peptide is designed that is cleaved by the protease. The peptide is labelled with dabcyl at the N terminus and Lucifer Yellow at the C-terminus, such that for an intact peptide the Lucifer Yellow fluorescence is quenched by the dabcyl. When the peptide is cut by BACE2, the quenching is removed and a fluorescent signal is generated. The assay was performed as described in Grueninger et al. 2002 at pH 4.5 using a substrate concentration of 5 μM. A FRET peptide based on the TMEM27 sequence was devised. dabcyl-QTLEFLKIPS-LucY (SEQ ID NO: 1). BACE2 had a high activity against this sequence, which is unrelated to the known APP-based substrates. Conversely, BACE1 had insignificant activity against this peptide. Inhibition Assay The assay is based on the principle that binding of the agonist to the RORγ causes a conformational change around helix 12 in the ligand binding domain, resulting in higher affinity for the co-activator peptide. The Fluorescein-D22 co-activator peptide used in the assay is recruited in the absence of a ligand. Binding of the co-activator peptide, causes an increase in the TR-FRET signal while binding of an inhibitor decreases the recruitment of the co-activator peptide, causing a decrease in the TR-FRET signal compared to a control with no test compound. The assay was performed using a two-step procedure, pre-incubation step with the test compound followed by the detection step on addition of the anti-GST tagged terbium (Tb) and fluorescein tagged fluorophores as the acceptor.Test compounds or reference compounds such as T0901317 (Calbiochem) were dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration. The final concentration of DMSO in the reaction was 4% (v/v). The assay mixture was prepared by mixing 10 nM of the GST-tagged ROR gamma ligand binding domain (LBD) in the assay buffer containing 25 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM DTT and 0.01% BSA with or without the desired concentration of the test compound. The reaction was incubated at 22° C. for 1 hour. The pre-incubation step was terminated by addition of the detection mixture containing 300 nM Fluorescein-D22 co-activator peptide and 10 nM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 minutes the reaction was further incubated for 1 hour at room temperature and read at 4° C. on an Infinite F500 reader as per the kit instructions (Invitrogen). Inhibition Assay Chinese hamster ovary cells are transfected with the human gene for amyloid precursor protein. The cells are plated at a density of 8000 cells/well into 96-well microtiter plates and cultivated for 24 hours in DMEM cell culture medium containing 10% FCS. The test compound is added to the cells at various concentrations, and the cells are cultivated for 24 hours in the presence of the test compound. The supernatants are collected, and the concentration of amyloid peptide 1-40 is determined using state of the art immunoassay techniques, for example sandwich ELISA, homogenous time-resolved fluorescence (HTRF) immunoassay, or electro-chemiluminescence immunoassay. The potency of the compound is calculated from the percentage of inhibition of amyloid peptide release as a function of the test compound concentration. Binding Assay The binding properties of the test compounds on adenosine receptors were determined in binding studies with radioligands. For this purpose, membrane preparations of the human adenosine receptor subtypes were produced from cell lines having recombinant receptor expression (CHO cells for the A1 receptor, HEK293 cells for the A2a, A2b and A3 receptors). The following radioligands were used in the experiments: [3H]-DPCPX for the A1 receptor, [3H]-CGS 21680 for the A2a receptor, [3H]-CPX for the A2b receptor and [125I]-AB-MECA for the A3 receptor. The test substances were each tested in 8 different concentrations and 2 repeat tests per concentration. The displacement of the particular radioligand by the test compound was expressed as percentage inhibition of the specific binding of the controls. Biological Assay The compounds of the invention can be tested for their ability to inhibit LSD1. The ability of the compounds of the invention to inhibit LSD1 can be tested as follows. Human recombinant LSD1 protein was purchased from BPS Bioscience Inc (catalog reference number 50100: human recombinant LSD1, GenBank accession no. NM_015013, amino acids 158-end with N-terminal GST tag, MW: 103 kDa). In order to monitor LSD1 enzymatic activity and/or its inhibition rate by our inhibitor(s) of interest, di-methylated H3-K4 peptide (Anaspec) was chosen as a substrate. The demethylase activity was estimated, under aerobic conditions, by measuring the release of H2O2 produced during the catalytic process, using the Amplex Red hydrogen peroxide/peroxidase assay kit (Invitrogen).Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, in the absence and/or in the presence of at least eight 3-fold serial dilutions of the respective test compound (e.g., from 0 to 75 uM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition. Within the experiment, each concentration of inhibitor was tested in duplicate. After leaving the enzyme interacting with the inhibitor, KM of di-methylated H3-K4 peptide was added to each reaction and the experiment was left for 30 minutes at 37° C. In the dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex Red reagent and horseradish peroxidase (HPR) solution were added to the reaction according to the recommendations provided by the supplier (Invitrogen), and left to incubate for 5 extra minutes at room temperature in the dark. A 1 uM H2O2 solution was used as a control of the kit efficiency. The conversion of the Amplex Red reagent to resorufin due to the presence of H2O2 in the assay, was monitored by fluorescence (excitation at 540 nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure level of H2O2 produced in the absence and/or in the presence of inhibitor. The maximum demethylase activity of LSD1 was obtained in the absence of inhibitor and corrected for background fluorescence in the absence of LSD1. The IC50 value of each inhibitor was calculated with GraphPad Prism Software. ChEBML_154319 Compound was evaluated for inhibitory activity against Peptide deformylase ChEMBL_89213 (CHEMBL699705) Inhibition constant (Ki) for human intestinal peptide carrier Monoamine Oxidase Assays Briefly, a fixed amount of MAO (0.25 μg for MAO-A and 0.5 μg for MAO-B) was incubated on ice for 15 minutes in the reaction buffer, in the absence and/or in the presence of various concentrations of inhibitor (e.g., from 0 to 50 μM, depending on the inhibitor strength). Tranylcypromine (Biomol International) was used as a control for inhibition.After leaving the enzyme(s) interacting with the inhibitor, 60 to 90 μM of kynuramine was added to each reaction for MAO-B and MAO-A assay respectively, and the reaction was left for 1 hour at 37° C. in the dark. The oxidative deamination of the substrate was stopped by adding 50 μL (v/v) of NaOH 2N. The conversion of kynuramine to 4-hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm, emission at 360 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units were used to measure levels of fluorescence produced in the absence and/or in the presence of inhibitor.The maximum of oxidative deamination activity was obtained by measuring the amount of 4-hydroxyquinoline formed from kynuramine deamination in the absence of inhibitor and corrected for background fluorescence in the absence of MAO enzymes. ChEBML_141731 The compound was evaluated for the inhibition of NADH dehydrogenase ChEBML_155080 The compound was evaluated for the inhibitory activity against plasmin ChEBML_208132 The compound was evaluated for the inhibitory activity against thrombin ChEBML_212352 The compound was evaluated for the inhibitory activity against trypsin ChEBML_41716 The compound was evaluated for the inhibition human of Butyrylcholinesterase ChEMBL_211356 (CHEMBL815872) The compound was evaluated for the anti-tubulin activity. ChEMBL_73023 (CHEMBL682625) Tested for the inhibition against the human dihydrofolate reductase Enzyme Inhibition Assay The inhibitory activities of compounds of the invention against the GSK 3 enzyme isoform (Invitrogen), are evaluated by determining the level of activation/phosphorylation of the target peptide. The GSK3-α protein (500 ng/mL, 2.5 uL) is mixed with the test compound (2.5 uL at either 4 ug/mL, 0.4 ug/mL, 0.04 ug/mL, or 0.004 ug/mL) for 2 hr at RT. The FRET peptide (8 uM, 2.5 uL), which is a phosphorylation target for GSK3α, and ATP (40 uM, 2.5 uL) are then added to the enzyme/compound mixture and the resulting mixture incubated for 1 hr. Development reagent (protease, 5 uL) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan Flash, ThermoFisher Scientific). Enzyme Inhibition The inhibitory activities of compounds of the invention against the GSK 3-alpha enzyme isoform (Invitrogen), are evaluated by determining the level of activation/phosphorylation of the target peptide. The GSK3-alpha protein (500 ng/mL, 2.5 uL) is mixed with the test compound (2.5 uL at either 4 ug/mL, 0.4 ug/mL, 0.04 ug/mL, or 0.004 ug/mL) for 2 hr at RT. The FRET peptide (8 uM, 2.5 uL), which is a phosphorylation target for GSK3alpha, and ATP (40 uM, 2.5 uL) are then added to the enzyme/compound mixture and the resulting mixture incubated for 1 hr. Development reagent (protease, 5 uL) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan Flash, ThermoFisher Scientific). Functional Peptidyl Prolyl Isomerase (PPlase) Spectrophotometric Assay Cyclophilins are enzymes that catalyse the cis-trans isomerisation of peptide bonds to the amino acid proline. This event is important in many biological processes, including protein folding and signal transduction. Cyclosporins and the compounds of the present invention inhibit this catalytic activity. The method to measure this activity and its inhibition is similar to that described by Jankowski (Analytical Biochemistry, 252, 2, 299-307 (1997)). The assay measures the cis to trans isomerisation of a peptide substrate catalysed by a PPlase enzyme using a UV/Vis spectrophotometer. This assay is a manual single cuvette-based assay. A first order rate equation is fitted to the absorbance data to obtain a rate constant. The catalytic rate is calculated from the enzymatic rate minus the background rate. The Ki (the concentration required to produce half maximum inhibition) for an inhibitor is obtained from the rate constant plotted against the inhibitor concentration. KinEASE Assay IC50 determinations for activated Akt1 were measured with the KinEASE assay (Cisbio) according to the manufacturer’s instructions. The kinases Akt1 (batch no. D8MN034U-L) was purchased from Millipore. 5 μL kinase solution (0.12 nM for Akt1) and 2.5 μL inhibitor solution (8% DMSO in HTRF buffer) were pre-incubated for 1 h before the reaction was started by addition of 2.5 μL of a solution containing ATP and substrate peptide. The final ATP and substrate concentrations were set at their respective Km values (50 μM and 250 nM, respectively, for Akt1). The biotinylated STK3 substrate peptide is then phosphorylated by Akt1 for 45 min. After completion of the reaction, 10 μL of a solution with an anti-phosphoserine/-threonine antibody labeled with Europium Cryptate and Streptavidin labeled with the fluorophore XL665 (0.5 μM for Akt1) were added simultaneously. The FRET between Europium Cryptate and XL665 was measured to quantify the extent of substrate pep
Phosphinic Peptide Inhibitor, 28 FII 2-benzyl-3-{[1-(2-acetamido-4-methylpentanoyl)pyrrolidin-2-yl](hydroxy)phosphoryl}propanoic acid The second fraction of the HPLC chromatogram. BDBM21464
2-benzyl-3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanoyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)propanoic acid Phosphinic Peptide Inhibitor, 34 FII The second fraction of the HPLC chromatogram. BDBM21470
Phosphinic Peptide Inhibitor, 26 BDBM21462 2-benzyl-3-[hydroxy(pyrrolidin-2-yl)phosphoryl]propanoic acid
3-{[1-(2-acetamido-4-methylpentanoyl)pyrrolidin-2-yl](hydroxy)phosphoryl}-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid The second fraction of the HPLC chromatogram. BDBM21473 Phosphinic Peptide Inhibitor, 40 FII
BDBM21459 3-[(1-aminoethyl)(hydroxy)phosphoryl]-2-benzylpropanoic acid Phosphinic Peptide Inhibitor, 18 CHEMBL51566
Phosphinic Peptide Inhibitor, 19 CHEMBL34068 3-[(1-amino-2-phenylethyl)(hydroxy)phosphoryl]-2-benzylpropanoic acid BDBM21460
Phosphinic Peptide Inhibitor, 27 BDBM21463 2-benzyl-3-{[1-(2-acetamidopropanoyl)pyrrolidin-2-yl](hydroxy)phosphoryl}propanoic acid
BDBM21455 3-({1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)-2-methylpropanoic acid Phosphinic Peptide Inhibitor, 14
Phosphinic Peptide Inhibitor, 41 FII The second fraction of the HPLC chromatogram. 3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanoyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid BDBM21474
3-{[1-(6-amino-2-acetamidohexanoyl)pyrrolidin-2-yl](hydroxy)phosphoryl}-2-benzylpropanoic acid BDBM21465 Phosphinic Peptide Inhibitor, 29
Phosphinic Peptide Inhibitor, 35 2-benzyl-3-{[1-(2-acetamido-4-methylpentanamido)-2-phenylethyl](hydroxy)phosphoryl}propanoic acid BDBM21471
CHEMBL36716 3-[(1-amino-3-methylbutyl)(hydroxy)phosphoryl]-2-benzylpropanoic acid Phosphinic Peptide Inhibitor, 20 BDBM21461
2-[({1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)methyl]-4-methylpentanoic acid Phosphinic Peptide Inhibitor, 13 BDBM21454
Phosphinic Peptide Inhibitor, 12 BDBM21452 2-benzyl-3-({1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)propanoic acid
Phosphinic Peptide Inhibitor, 16 BDBM21457 2-benzyl-3-[(1-{[(benzyloxy)carbonyl]amino}-2-phenylethyl)(hydroxy)phosphoryl]propanoic acid
The second fraction of the HPLC chromatogram. Phosphinic Peptide Inhibitor, 44 FII BDBM21475 3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanamido]-3-methylbutyl}(hydroxy)phosphoryl)-2-[(3-phenyl-1,2-oxazol-5-yl)methyl]propanoic acid
Phosphinic Peptide Inhibitor, 32 2-benzyl-3-{[1-(2-acetamido-3-phenylpropanoyl)pyrrolidin-2-yl](hydroxy)phosphoryl}propanoic acid BDBM21468
Phosphinic Peptide Inhibitor, 33 2-benzyl-3-{[1-(2-acetamido-3-methylbutanoyl)pyrrolidin-2-yl](hydroxy)phosphoryl}propanoic acid BDBM21469
2-benzyl-3-[(1-{[(benzyloxy)carbonyl]amino}ethyl)(hydroxy)phosphoryl]propanoic acid Phosphinic Peptide Inhibitor, 15 BDBM21456
BDBM21466 5-{2-[(2-benzyl-2-carboxyethyl)(hydroxy)phosphoryl]pyrrolidin-1-yl}-4-acetamido-5-oxopentanoic acid Phosphinic Peptide Inhibitor, 30
2-benzyl-3-[(1-{[(benzyloxy)carbonyl]amino}-3-methylbutyl)(hydroxy)phosphoryl]propanoic acid BDBM21458 Phosphinic Peptide Inhibitor, 17
Phosphinic Peptide Inhibitor, 31 BDBM21467 2-benzyl-3-({1-[2-acetamido-3-(4-hydroxyphenyl)propanoyl]pyrrolidin-2-yl}(hydroxy)phosphoryl)propanoic acid
ATX inhibitor 2 BDBM103560
BDBM104895 US8569313, Inhibitor 2
BDBM214779 OPRT inhibitor, 2
BDBM237291 CA inhibitor, 2
BDBM65493 eIF4A3 inhibitor, 2
BDBM65496 SmNACE inhibitor, 2
BDBM92346 GSK3 Inhibitor, 2
BDBM92357 HGXPRT Inhibitor, 2
BDBM92442 MMP Inhibitor, 2
BTK inhibitor, 2 BDBM225237
Benzimidazole Inhibitor, 2 BDBM93209
CB2 Inhibitor, 2 BDBM93026
CDK Inhibitor, 2 BDBM81429
MgrA inhibitor, 2 BDBM81553
PDK1 inhibitor, 2 BDBM92402
Phosphinate inhibitor 2 BDBM81616
TIM inhibitor, 2 BDBM246597
hCA inhibitor, 2 BDBM236545
hCA inhibitor, 2 BDBM60962
mtFabH inhibitor, 2 BDBM233055
Phosphinic Peptide Inhibitor, 36 2-benzyl-3-({1-[2-acetamido-3-(1H-imidazol-4-yl)propanamido]-3-methylbutyl}(hydroxy)phosphoryl)propanoic acid BDBM21472