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Simple Search Results

Query String: Helical peptide segments from the LXXLL motif region

paired helical filament-tau
c-c motif chemokine 2
c-c motif chemokine 4
pctaire-motif protein kinase 3
tripartite motif-containing protein 58
tripartite motif-containing protein 59
breakpoint cluster region protein
bromodomain and extra-terminal motif (bet)
chemokine (c-c motif) receptor 1
nucleoside diphosphate-linked moiety x motif 9
transmembrane bax inhibitor motif-containing protein 6
breakpoint cluster region protein [1-693]
adam metallopeptidase with thrombospondin type 1 motif 4
adam metallopeptidase with thrombospondin type 1 motif, 5
cat eye syndrome critical region protein 2
cat eye syndrome critical region protein 5
ig lambda chain v-vi region eb4
translocated promoter region and nuclear basket protein
rna-binding motif protein, x chromosome, n-terminally processed
breakpoint cluster region protein/tyrosine-protein kinase abl1
glioma tumor suppressor candidate region gene 1 protein
mhc class ii region expressed gene ke2, isoform cra_a
tyrosine-protein kinase abl1 [t315i]/breakpoint cluster region protein
peptide deformylase
peptide enifple
peptide hd2
peptide hippen

BDBM86193 Alpha-Helical CRF CAS_0 NSC_0
BDBM50288457 CHEMBL317974 macrocyclic tripeptide motif

Yin, H; Hamilton, AD Terephthalamide derivatives as mimetics of the helical region of Bak peptide target Bcl-xL protein. Bioorg Med Chem Lett 14: 1375-9 (2004)
Mita, Y; Dodo, K; Noguchi-Yachide, T; Miyachi, H; Makishima, M; Hashimoto, Y; Ishikawa, M LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators. Bioorg Med Chem Lett 20: 1712-7 (2010)
Murage, EN; Schroeder, JC; Beinborn, M; Ahn, JM Search for alpha-helical propensity in the receptor-bound conformation of glucagon-like peptide-1. Bioorg Med Chem 16: 10106-12 (2008)
Luo, Q; Ma, Y; Liang, H; Feng, Y; Liu, N; Lian, C; Zhu, L; Ye, Y; Liu, Z; Hou, Z; Chen, S; Wang, Y; Dai, C; Song, C; Zhang, M; He, Z; Xing, Y; Zhong, W; Li, S; Wu, J; Lu, F; Yin, F; Li, Z Covalent Peptide LSD1 Inhibitor Specifically Recognizes Cys360 in the Enzyme-Active Region. J Med Chem 66: 15409-15423 (2023)
Guerlavais, V; Sawyer, TK; Carvajal, L; Chang, YS; Graves, B; Ren, JG; Sutton, D; Olson, KA; Packman, K; Darlak, K; Elkin, C; Feyfant, E; Kesavan, K; Gangurde, P; Vassilev, LT; Nash, HM; Vukovic, V; Aivado, M; Annis, DA Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized α-Helical Peptide in Clinical Development. J Med Chem 66: 9401-9417 (2023)
Gao, Y; Voigt, J; Zhao, H; Pais, GC; Zhang, X; Wu, L; Zhang, ZY; Burke, TR Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif. J Med Chem 44: 2869-78 (2001)
Anananuchatkul, T; Tsutsumi, H; Miki, T; Mihara, H hDM2 protein-binding peptides screened from stapled α-helical peptide phage display libraries with different types of staple linkers. Bioorg Med Chem Lett 30: (2020)
Liu, D; Yang, B; Cao, R; Huang, Z A chemical strategy to promote helical peptide-protein interactions involved in apoptosis. Bioorg Med Chem Lett 15: 4467-9 (2005)
Khoo, KK; Wilson, MJ; Smith, BJ; Zhang, MM; Gulyas, J; Yoshikami, D; Rivier, JE; Bulaj, G; Norton, RS Lactam-stabilized helical analogues of the analgesicµ-conotoxin KIIIA. J Med Chem 54: 7558-66 (2011)
Martinez, J; Magous, R; Lignon, MF; Laur, J; Castro, B; Bali, JP Synthesis and biological activity of new peptide segments of gastrin exhibiting gastrin antagonist property. J Med Chem 27: 1597-601 (1985)
Mita, Y; Dodo, K; Noguchi-Yachide, T; Hashimoto, Y; Ishikawa, M Structure-activity relationship of benzodiazepine derivatives as LXXLL peptide mimetics that inhibit the interaction of vitamin D receptor with coactivators. Bioorg Med Chem 21: 993-1005 (2013)
Liu, G; Liu, G; Hou, R; Hou, R; Xu, L; Xu, L; Zhang, X; Zhang, X; Yan, J; Yan, J; Xing, C; Xing, C; Xu, K; Xu, K; Zhuang, C; Zhuang, C Crystallography-Guided Optimizations of the Keap1-Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides. J Med Chem 65: 8289-8302 (2022)
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M'Kadmi, C; Cabral, A; Barrile, F; Giribaldi, J; Cantel, S; Damian, M; Mary, S; Denoyelle, S; Dutertre, S; Péraldi-Roux, S; Neasta, J; Oiry, C; Banères, JL; Marie, J; Perello, M; Fehrentz, JA N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor. J Med Chem 62: 965-973 (2019)
Peng, YH; Shiao, HY; Tu, CH; Liu, PM; Hsu, JT; Amancha, PK; Wu, JS; Coumar, MS; Chen, CH; Wang, SY; Lin, WH; Sun, HY; Chao, YS; Lyu, PC; Hsieh, HP; Wu, SY Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J Med Chem 56: 3889-903 (2013)
Xu, X; Weitzberg, M; Keyes, RF; Li, Q; Wang, R; Wang, X; Zhang, X; Frevert, EU; Camp, HS; Beutel, BA; Sham, HL; Gu, YG The synthesis and structure-activity relationship studies of selective acetyl-CoA carboxylase inhibitors containing 4-(thiazol-5-yl)but-3-yn-2-amino motif: polar region modifications. Bioorg Med Chem Lett 17: 1803-7 (2007)
Zawahir, Z; Neamati, N Inhibition of HIV-1 integrase activity by synthetic peptides derived from the HIV-1 HXB2 Pol region of the viral genome. Bioorg Med Chem Lett 16: 5199-202 (2006)
Kreutter, KD; Lu, T; Lee, L; Giardino, EC; Patel, S; Huang, H; Xu, G; Fitzgerald, M; Haertlein, BJ; Mohan, V; Crysler, C; Eisennagel, S; Dasgupta, M; McMillan, M; Spurlino, JC; Huebert, ND; Maryanoff, BE; Tomczuk, BE; Damiano, BP; Player, MR Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif. Bioorg Med Chem Lett 18: 2865-70 (2008)
Novick, PA; Lopes, DH; Branson, KM; Esteras-Chopo, A; Graef, IA; Bitan, G; Pande, VS Design of β-amyloid aggregation inhibitors from a predicted structural motif. J Med Chem 55: 3002-10 (2012)
Lima, LM; Silva, Vde A; Palmieri, Lde C; Oliveira, MC; Foguel, D; Polikarpov, I Identification of a novel ligand binding motif in the transthyretin channel. Bioorg Med Chem 18: 100-10 (2010)
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Erdeljac, N; Thiehoff, C; Jumde, RP; Daniliuc, CG; Höppner, S; Faust, A; Hirsch, AKH; Gilmour, R Validating the 1,2-Difluoro Motif As a Hybrid Bioisostere of CF J Med Chem 63: 6225-6237 (2020)
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Di Maro, S; Trotta, AM; Brancaccio, D; Di Leva, FS; La Pietra, V; Ieranò, C; Napolitano, M; Portella, L; D'Alterio, C; Siciliano, RA; Sementa, D; Tomassi, S; Carotenuto, A; Novellino, E; Scala, S; Marinelli, L Exploring the N-Terminal Region of C-X-C Motif Chemokine 12 (CXCL12): Identification of Plasma-Stable Cyclic Peptides As Novel, Potent C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonists. J Med Chem 59: 8369-80 (2016)
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Klee, N; Wong, PE; Baragaña, B; Mazouni, FE; Phillips, MA; Barrett, MP; Gilbert, IH Selective delivery of 2-hydroxy APA to Trypanosoma brucei using the melamine motif. Bioorg Med Chem Lett 20: 4364-6 (2010)
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Wildemann, D; Erdmann, F; Alvarez, BH; Stoller, G; Zhou, XZ; Fanghänel, J; Schutkowski, M; Lu, KP; Fischer, G Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries. J Med Chem 49: 2147-50 (2006)
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Imamura, Y; Umezawa, N; Osawa, S; Shimada, N; Higo, T; Yokoshima, S; Fukuyama, T; Iwatsubo, T; Kato, N; Tomita, T; Higuchi, T Effect of helical conformation and side chain structure on γ-secretase inhibition by β-peptide foldamers: insight into substrate recognition. J Med Chem 56: 1443-54 (2013)
Perreault, S; Arjmand, F; Chandrasekhar, J; Hao, J; Keegan, KS; Koditek, D; Lepist, EI; Matson, CK; McGrath, ME; Patel, L; Sedillo, K; Therrien, J; Till, NA; Tomkinson, A; Treiberg, J; Zherebina, Y; Phillips, G Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif. ACS Med Chem Lett 11: 1236-1243 (2020)
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Probst, GD; Bowers, S; Sealy, JM; Stupi, B; Dressen, D; Jagodzinska, BM; Aquino, J; Gailunas, A; Truong, AP; Tso, L; Xu, YZ; Hom, RK; John, V; Tung, JS; Pleiss, MA; Tucker, JA; Konradi, AW; Sham, HL; Jagodzinski, J; Toth, G; Brecht, E; Yao, N; Pan, H; Lin, M; Artis, DR; Ruslim, L; Bova, MP; Sinha, S; Yednock, TA; Gauby, S; Zmolek, W; Quinn, KP; Sauer, JM Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region. Bioorg Med Chem Lett 20: 6034-9 (2010)
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AlphaScreen Assay AlphaScreen was used with the aim of identifying novel modulators by taking advantage of the bimolecular interaction prevailing between FXR and the LXXLL motif present in the NR box of the steroid receptor coactivator 1 (SRC-1).Human FXR-LBD-GST was incubated with increasing concentrations of the indicated ligands in the presence of biotinylated LXXLL SRC-1 peptide. The AlphaScreen signal increases when the complex receptor-coactivator is formed.
ChEMBL_48921 (CHEMBL660751) Binding affinity towards 23-nt RNA oligonucleotide from the 5'-untranslated region of the cholestery ester transfer protein (CETP)
ChEMBL_2469668 Antagonist activity at C-terminal RLucII-fused human ER-alpha expressed in HEK293T cells co-expressing CoA-YFP-fused LXXLL coactivator motif from NCOA2 in presence of E2 by BRET assay
ChEMBL_304408 (CHEMBL831813) Effective concentration for recruitment of SRC-1 LxxLL-containing peptide to human Farnesoid X receptor
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_35453 (CHEMBL643724) Inhibitory concentration against B-Cell Lymphoma xL (Bcl-xL) Bak-peptide binding region
ChEMBL_815757 (CHEMBL2025841) Displacement of fluorescein-labeled phosphotyrosine-peptide derived from the interleukin-6 receptor subunit gp130 from the STAT3 after 15 mins by fluorescent polarization assay
MAO-A and MAO-B Assay The MAO-A and MAO-B is purchased from Active Motif (Cat#31502, Cat#31503). Biochemical Kit is purchased from Promega (MAO-Glo Assay, V1402). The inhibition of selectivity assay was preformed in light of the manufacturer's protocol.
ChEMBL_2071588 (CHEMBL4727122) Displacement of propidium iodide from PAS region of electric eel AChE by fluorescence assay
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.
ChEMBL_461 (CHEMBL615691) The ability of the peptide to inhibit the binding of 50 pM [125I]gastrin releasing peptide to intact S-3T3 cells
ChEMBL_2112634 (CHEMBL4821484) Displacement of [3H]-ketanserin from Wistar rat frontal region 5-HT2AR incubated for 30 mins
ChEMBL_851510 (CHEMBL2156749) Displacement of [3H]ABP688 from human mGluR5a transmembrane region expressed in mouse L(tk-) cells
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.
ChEMBL_2112633 (CHEMBL4821483) Displacement of [3H]-5-OH-DPAT from Wistar rat frontal region 5-HT1AR incubated for 30 mins
Inhibition Assay NSC-87877 ranked among top 10% (175th) of the compounds with the best GLIDE scores for the docking to the human Shp2 PTP domain in our virtual screening of 2368 3D structures derived from the NCI Diversity Set. Computer docking of NSC-87877 (FIG. 2) suggested that the B-ring sulfonic acid group forms hydrogen bond with the backbone NH group of Arg-465. Arg-465 is a conserved residue in the PTP signature motif (motif 9) VHCSXGXGR[T/S]G located at the base of the PTP catalytic cleft (Andersen et al., 2001). The A-ring sulfonic acid forms hydrogen bonds with the side-chain NH3 group of Lys-280 and the side-chain NH2 group of Asn-281. Lys-280/Asn-281 are non-conserved PTP residues located adjacent to the phosphotyrosine recognition loop (motif 1) (Andersen et al., 2001). The interaction between aromatic rings of the compound and the protein contributes to the binding through hydrophobic stabilization.
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_770205 (CHEMBL1832995) Displacement of H4Ac4 peptide from first bromodomain of human BRD2 by peptide displacement assay
ChEMBL_770206 (CHEMBL1832996) Displacement of H4Ac4 peptide from first bromodomain of human BRD4 by peptide displacement assay
ChEMBL_2057667 (CHEMBL4712668) Displacement of propidium iodide from PAS-region of electric eel AChE assessed as dissociation constant by spectrofluorimetric analysis
ChEBML_146550 The ability to displace [3H]-naloxone from the Opioid receptor mu isolated from rat brain membrane.
ChEMBL_36341 (CHEMBL650168) Displacement of [3H]-AII from the Angiotensin II receptor isolated from the liver of rats
ChEMBL_303746 (CHEMBL829789) Ability to inhibit the hydrolysis of chromogenic 4-phenylazophenyl ester from the peptide fragment Ac- DTEDVVP(Nva)-O-4-PAP in a HCV protease continuous assay
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.
ChEMBL_1517687 (CHEMBL3620075) Inhibition of kelch domain of Keap1 (unknown origin) interaction to high affinity ETGE motif from Nrf2 by fluorescence polarization assay
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_303773 (CHEMBL830130) Ability to inhibit the hydrolysis of chromogenic 4-chlorophenylbutyric acid ester from the peptide fragment Ac- DTEDVVP(Nva)-O-4-PAP in a HCV protease continuous assay
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.
ChEBML_148701 The ability to displace [3H]naloxone from the Opioid receptor mu 1 isolated from rat brain membrane.
ChEBML_148837 Ability to displace [3H]naloxone from the Opioid receptor mu 1 isolated from the rat brain membranes.
ChEMBL_146550 (CHEMBL754969) The ability to displace [3H]-naloxone from the Opioid receptor mu isolated from rat brain membrane.
ChEMBL_146552 (CHEMBL754970) The ability to displace [3H]naloxone from the opioid receptor mu isolated from rat brain membrane.
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).
Protease Inhibition Assay The Ki values were obtained from the IC50 values estimated from an inhibitor dose-response curve with the spectroscopic assay and the chromogenic substrate.
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. IC50 values were obtained from dose response curves.
MK-2 IC50 Value Determination The phosphorylation of HSP27 peptide by MAPKAPK2 was measured using an anion exchange resin capture assay method. The reaction was carried out in reaction buffer containing enzyme and test compound in the presence of the HSP-peptide with [gamma-33P]ATP /ATP. After the reaction was terminated and [gamma-33P]ATP was removed from solution by the addition of AG 1X8 ion exchange resin. An aliquot was removed from the quenched reaction mixture and added to a 96-well plate. Microscint-40 (Packard) was added and the amount of phosphorylated-peptide was determined.
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.
ChEMBL_1721968 (CHEMBL4136968) Agonist activity at His tagged RORgammat LBD (unknown origin) expressed in baculovirus infected sf9 cells assessed as biotinylated-LXXLL peptide coactivator recruitment incubated for overnight by TR-FRET Assay
ChEMBL_2272602 Displacement of biotinylated Bim peptide from Bcl-2 (unknown origin)
ChEMBL_2432156 Displacement of tetra-acetylated H4 peptide from ATAD2B (unknown origin)
ChEMBL_811654 (CHEMBL2014167) Displacement of [125I]peptide YY from human NPY5 receptor
ChEMBL_148701 (CHEMBL751073) The ability to displace [3H]naloxone from the Opioid receptor mu 1 isolated from rat brain membrane.
ChEMBL_148837 (CHEMBL753955) Ability to displace [3H]naloxone from the Opioid receptor mu 1 isolated from the rat brain membranes.
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.
ChEMBL_146553 (CHEMBL754971) The ability to displace [3H]naloxone from the opioid receptor mu isolated from rat brain membrane; >= no displacement
ChEMBL_2440286 Displacement of BRC4-biotinylated peptide from human RAD51 by competitive ELISA
ChEMBL_770203 (CHEMBL1832993) Displacement of H3K56Ac from human CREBBP by peptide displacement assay
LANCE Ultra Assay The LANCE Ultra assay kit was purchased from PerkinElmer. The ULight-MBP peptide, Europium labeled Antibody and LANCE Detection buffer were purchased from PerkinElmer. The APT and dimethylsulfoxide were purchased from Sigma-Aldrich. The 5× Kinase buffer were purchased from Invitrogen. The MAP kinase 1 (Mek1), inactive Erk1 were purchased from Millipore. A Mek1 kinase assay (LANCE, PerkinElmer) was developed for supporting compound profiling and lead optimization. In this assay, un-phosphorylated/inactive Erk1 (Millipore) was used as the substrate for Mek1 (Millipore). Then the phosphorylated Erk1 was able to phosphorylate ULight-MBP peptide (PerkinElmer). The phosphorylated peptide was detected by Europium-anti-phospho-MBP (PerkinElmer). In a reaction, the activity of Mek1 (0.5 nM) was measured in a buffer containing 50 μM ATP, 2 nM inactive Erk1, 2 nM ULight-MBP peptide, and a compound for 90 min at 23° C. After quenching the reaction with xxx, 2 nM Europium-anti-phospho-MBP was added to the reaction mixture and incubated for 60 min, followed by a detection using EnVision Multilabel Plate Reader (PerkinElmer).
PPIase Assay The promising ligand from the results obtained from ESI-MS assay are subjected to PPIase in vitro assay. The PPIase assay assesses the abil9ity of ligands to inhibit the PPIase activity of CypA.
ChEMBL_149149 (CHEMBL759240) The ability to displace [3H]naloxone from the Opioid receptor mu 1 isolated from rat brain membrane; >= no displacement
ChEBML_164495 Inhibitory activity against peptide binding to the RRE RNA was determined
ChEMBL_154313 (CHEMBL762798) Inhibition of the isolated native E. coli peptide deformylase (PDF)
ChEBML_212946 Binding affinity to uridine kinase from L1210. was determined from the dixon plot
ChEBML_212947 Binding affinity to uridine kinase from L1210. was determined from the dixon plot
ChEBML_217700 The compound was evaluated for the inhibition of dTMP synthetase from Lactobacillus casei
ChEBML_30523 The compound was tested for the inhibition of alanine racemase from Pseudomonas aeruginosa
ChEMBL_1884179 (CHEMBL4385761) Inhibition of tau-tau binding (unknown origin) assessed as increase in dissolved paired helical filaments
ChEMBL_1736592 (CHEMBL4152128) Inhibition of Keap1 Kelch domain (unknown origin) /Nrf2 (unknown origin) interaction using fluorescein-labeled 9-mer peptide containing NRF2 Neh2 domain ETGE motif by fluorescence anisotropy assay
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.
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.
Mobility-Shift kinase assay Compounds of the examples provided herein were assessed for their ability to inhibit Syk kinase by utilizing Caliper Life Sciences' proprietary LabChip technology. The off-chip incubation mobility-shift kinase assay uses a microfluidic chip to measure the conversion of a fluorescent peptide substrate to a phosphorylated product. The reaction mixture, from a microtiter plate well, is introduced through a capillary sipper onto the chip, where the nonphosphorylated substrate and phosphorylated product are separated by electrophoresis and detected via laser induced fluorescence. The signature of the fluorescence signal over time reveals the extent of the reaction. The phosphorylated product migrates through the chip faster than the non-phosphorylated substrate, and signals from the two forms of the peptide appear as distinct peaks.
ChEMBL_149148 (CHEMBL759239) The ability to displace [3H]naloxone from the Opioid receptor mu 1 isolated from rat brain membrane; >= absolutely no % change
ChEBML_155034 Inhibitory activity against human PDE4A expressed isoform using construct representing the common region of spliced variants as GST-fusion protein in Sf9 cells.
ChEMBL_744058 (CHEMBL1768208) Displacement of biotin-labeled JIP1 peptide from JNK1 by DELFIA assay
ChEMBL_807449 (CHEMBL1958571) Displacement of acetylated histone peptide from BRD2-BD1,2 by FRET assay
ChEMBL_807450 (CHEMBL1958572) Displacement of acetylated histone peptide from BRD3-BD1,2 by FRET assay
ChEMBL_807451 (CHEMBL1958573) Displacement of acetylated histone peptide from BRD4-BD1,2 by FRET assay
Pin1 Inhibition Assay Assay was carried out measuring the MCA fluorescence using Suc-Ala-Glu-Pro-Phe-MCA as substrate purchased from Japan Peptide Institute Co.
ChEBML_104575 Ability to inhibit the matrix metalloprotease-3 by method of Knight et al using the fluorogenic peptide substrate.
ChEBML_106803 Ability to inhibit the matrix metalloprotease-2 by method of Knight et al using the fluorogenic peptide substrate.
Fluorescent Peptide Displacement Assay Test compound was incubated for 15 minutes with 30 nM peptide fluorescein-FMDYWEGLN (Fl 9mer) and 120 nM (glycine-HDM2 17-125) in assay buffer. The polarization of the fluorescein label was measured by excitation at 485 nm and emission at 530 nm. Percent inhibition was calculated from the decrease in the fluorescence polarization of the labeled peptide upon displacement from HDM2 by the compounds, using buffer with Fl 9mer but without HDM2 as background. Data were analyzed by non-linear least squares fitting to a hyperbolic binding function. The measured IC50s of the p53 wild-type (QETFSDLWKLLP) and optimized (MPRFMDYWEGLN) peptides are 2000 and 250 nM, respectively. Under these conditions, the IC50 is 2.5 fold higher than the dissociation binding constant (Kd).
In Vitro Kinase Assay The IC50 for the different compounds was determined with Invitrogen Z'-LYTE kinase assay kit Ser/Thr 1 peptide PV3174 by following the manufacturer's instructions. To determine the IC50 of receptor tyrosine kinase, an assay based on the ELISA principle with kinases from Biomol (N-terminally fused to GST), POD-coupled antibody from Calbiochem (PY20)) and BM chem chemiluminescence ELISA substrate from Roche was performed.
ChEMBL_164495 (CHEMBL771472) Inhibitory activity against peptide binding to the RRE RNA was determined
Protease Inhibition Assay The inhibition assays were performed in microtiter plate wells by mixing enzyme and fluorescent peptide substrate in the presence of inhibitor compounds. The increase of fluorescence was detected using fluorimeter-luminometer. Ki values were calculated from the IC50 values estimated from a dose-response curve with the fluorescent assay using the equation Ki = (IC50 - [E]/2)/ (1 +[S]/Km), where [E] and [S] are the protease and substrate concentrations.
ChEBML_139952 Displacement of [3H]-Pz (pirenzepine) from the muscarinic receptor M1 of the rat hippocampus
ChEMBL_217700 (CHEMBL821239) The compound was evaluated for the inhibition of dTMP synthetase from Lactobacillus casei
ChEMBL_28150 (CHEMBL644105) Evaluated for the in vitro inhibition of the Acetylcholinesterase (AChE) from human erythrocytes
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 Assay A coupled-enzyme assay was used to quantify the ADP generated in the kinase reaction with S6 peptide (RRRLSSLRA) as the phosphoacceptorsubstrate.
EGFR IC50 Determination The kinase reaction for EGFR consisted of BSA-supplemented kinase buffer, kinase, peptide, and ATP. For IC50 determinations, 10 different concentrations (ranging from 0.1 nM to 10 uM) of inhibitor were used in duplicate. Each experiment was repeated at least twice. 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.
PKA In Vitro Enzyme Assay The recombinant alpha catalytic subunit of bovine PKA was assayed with a peptide substrate and test compound in the presence of 40 uM ATP/ [gamma-33P]ATP in 96-well plates. IC50 is the concentration of inhibitor that inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from [gamma-33P] labeled ATP to substrate peptide. IC50 values were determined from an eight-point concentration range run in duplicate and calculated in GraphPad Prism 4.00.
PKB In Vitro Enzyme Assay The purified PKB beta enzyme was assayed with a peptide substrate and test compound in the presence of 30 uM ATP/ [gamma-33P]ATP in 96-well plates. IC50 is the concentration of inhibitor that inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from [gamma-33P] labeled ATP to substrate peptide. IC50 values were determined from an eight-point concentration range run in duplicate and calculated in GraphPad Prism 4.00.
ChEMBL_155034 (CHEMBL765476) Inhibitory activity against human PDE4A expressed isoform using construct representing the common region of spliced variants as GST-fusion protein in Sf9 cells.
ChEMBL_155036 (CHEMBL765478) Inhibition of human Phosphodiesterase 4A isoform using construct representing the common region of spliced variants expressed as GST-fusion proteins in Sf9 cells.
ROCK 1 Kinase Activity Assay The assay of Rock-1 activity involved incubation with peptide substrate and ATP/[gamma-33P] ATP, the subsequent incorporation of 33P into the peptide was quantified by Scintillation Proximity Assay (SPA - Amersham Pharmacia).
ChEBML_208276 Evaluated for the inhibition of trehalase from porcine kidneys
ChEMBL_1804490 (CHEMBL4303093) Displacement of [3H]-DTG from the Sigma2 receptor
ChEMBL_1804491 (CHEMBL4303094) Displacement of [3H]-pentazocin from the Sigma1 receptor
ChEMBL_438659 (CHEMBL888990) Displacement of [125I] ITAC from the CXCR3 receptor
ChEMBL_48915 (CHEMBL660745) Inhibition of the Pancreatic Cholesterol Esterase from porcine
FRET-Based Assay The protease activity of the full-length NS3-NS4a and the protease domain were measured using a FRET-based assay using a peptide substrate derived from the NS4A/B cleavage site and labeled at one end with a quencher (QXL520) and at the other with a fluorophore (5-FAMsp; Anaspec).
ChEMBL_1287023 (CHEMBL3111334) Displacement of H4Ac4 peptide from CECR2 bromodomain (unknown origin) by AlphaScreen assay
ChEMBL_217807 (CHEMBL823263) Displacement of a non-peptide radioligand from human recombinant alphaV-beta3 integrin
ChEMBL_439337 (CHEMBL888453) Displacement of FAM-Bim peptide from human Bcl2 by fluorescence polarization assay
ChEMBL_439339 (CHEMBL888455) Displacement of FAM-Bim peptide from human Mcl1 by fluorescence polarization assay
ChEMBL_537290 (CHEMBL985386) Displacement of fluorescein labeled Bax peptide from Bcl2 by fluorescence polarization assay
ChEMBL_639438 (CHEMBL1168411) Displacement of fluorescently-tagged BH3 peptide from Bcl-XL by fluorimetric assay
ChEMBL_807448 (CHEMBL1958570) Displacement of acetylated histone peptide from CREBBP by luminescence proximity homogenous assay
ChEMBL_811269 (CHEMBL2015221) Displacement of fluorescein-labeled p53 peptide from HDM2 by fluorescence polarization assay
ChEMBL_971499 (CHEMBL2406561) Displacement of [125I]MCH peptide from human MCHR1 expressed in CHOK1 cells
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.
Enzyme Assay The Aurora assays described here are performed on two Caliper Life Sciences systems: the LC3000 and the Desktop Profiler. These provide data on enzyme activity via measurement of the relative amounts of phosphorylated or unphosphorylated fluorescently labelled substrate peptide at the end of an enzymatic reaction. These different states of peptide are resolved by applying a potential difference across the sample. The presence of the charged phosphate group on the product (as opposed to the substrate) causes a different peptide mobility between the two peptides. This is visualized by excitation of the fluorescent label on the substrate and product peptides and represented as peaks within the analysis software.
ChEBML_3868 The compound was tested for the inhibition of Arachidonate 5-lipoxygenase purified from porcine leukocytes.
ChEMBL_41588 (CHEMBL654882) Compound was evaluated for the in vitro inhibition of the Butyrylcholinesterase from horse serum
Enzyme Inhbition Assay Enzyme activity is measured by observing the increase in fluorescence intensity caused by cleavage of a peptide substrate containing a fluorophore whose emission is quenched in the intact peptide.
Competitive Binding Assay Fluorescence polarization competitive binding assays were used to measure the IC50s of compounds binding to the different SH2 domains. The difference in polarization values of fluorescein-conjugated peptide reflects the bound and unbound state of the probe. IC50s were calculated based on the binding of the fluorescein-conjugated peptide to the protein with compound addition relative to vehicle-alone control samples.
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.).
Enzymatic Assay Compounds were tested for their inhibition of the addition of L-Ala, D-Glu, L-Lys or D-Ala-D-Ala to nucleotide precursors catalyzed by MurC from Escherichia coli, MurD from E. coli, MurE from Staphylococcus aureus, and MurF from E coli. The detection of the orthophosphate generated during the reaction was based on the colorimetric Malachite green method.
GW0385 Assay The assay method employed kinetic determinations of values for k1 and k-1, from which value of inhibition constant (Ki ) was determined (k-1/k1). The k1 is calculated from spectrofluorometric data in the presence of saquinavir. The k-1 is calculated from the time course for displacement of [3H]GW0385 from E[3H]GW0385 by nonlabeled GW0385.
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).
Measurement of Biochemical Activity of Compounds In order to assess the activity of chemical compounds against the relevant kinase of interest, the Caliper LifeSciences electrophoretic mobility shift technology platform is used. Fluorescently labeled substrate peptide is incubated in the presence of kinase and ATP so that a reflective proportion of the peptide is phosphorylated. At the end of the reaction, the mix of phosphorylated (product) and non-phosphorylated (substrate) peptides are passed through the microfluidic system of the Caliper EZ Reader 2, under an applied potential difference. The presence of the phosphate group on the product peptide provides a difference in mass and charge between those of the substrate peptide, resulting in a separation of the substrate and product pools in the sample. As the pools pass a LEDS within the instrument, these pools are detected and resolved as separate peaks. The ratio between these peaks therefore reflects the activity of the chemical matter at that concentration in that well, under those conditions.
Measurement of Biochemical Activity of Compounds In order to assess the activity of chemical compounds against the relevant kinase of interest, the Caliper LifeSciences electrophoretic mobility shift technology platform was used. Fluorescently labeled substrate peptide was incubated in the presence of kinase and ATP so that a reflective proportion of the peptide was phosphorylated. At the end of the reaction, the mix of phosphorylated (product) and non-phosphorylated (substrate) peptides were passed through the microfluidic system of the Caliper EZ Reader 2, under an applied potential difference. The presence of the phosphate group on the product peptide provides a difference in mass and charge between those of the substrate peptide, resulting in a separation of the substrate and product pools in the sample. As the pools pass a LEDS within the instrument, these pools are detected and resolved as separate peaks. The ratio between these peaks therefore reflects the activity of the chemical matter at that concentration in that well, under those conditions.
ChEBML_35004 Binding affinity was determined based on the displacement of [125]r-ANF (99-126) from binding sites on mouse fibroblasts (NIH 3T3) cells (Atrionatriuretic peptide receptor C).
ChEMBL_155035 (CHEMBL765477) Inhibitory concentration against human PDE4A isoform using a construct representing the common region of spliced variants expressed as GST-fusion protein in Sf9 cells
Fluorescence Polarization Cell-Free Homogeneous Dose Retest to Confirm Inhibitors of the LANA Histone H2A/H2B Interaction Primary Collaborators: Kenneth Kaye,Brigham & Womens,Boston MA,kkaye@rics.bwh.harvard.edu,617-525-4256 Chantal Beauchemin,Brigham & Womens,Boston MA,cbeauchemin@rics.bwh.harvard.edu,617-525-4256 Keywords: KSHV, LANA, fluorescence polarization, nucleosomes, viral persistence Assay Overview: Screening for inhibitors that reduce or prevent the binding of LANA to the acidic region of the H2A/H2B histone dimer interface. Synthetic LANA peptide is labeled with an amino terminal FITC fluorophore linked via a beta alanine residue. The peptide contains the first 23 amino acids of the LANA protein that is essential for binding to the H2A/H2B interface. Nucleosomes were purifed from chicken Erythrocytes as a source of intact H2A/H2B dimers. Fluorescence is measured in the S and P planes with a Perkin Elmer Viewlux after 1 hour incubation. Expected Outcome: Compounds will be identified that inhibit the interaction of LANA 1-23 peptide with purified nucleosomes (containing H2A/H2B histone
ChEMBL_2266265 Inverse agonist activity at 6His-tagged RORA LBD (unknown origin) expressed in Escherichia coli assessed as inhibition of biotinylated SRC1-2 derived CPSSHSSLTERHKILHRLLQEGSPS-NH2 containing LXXLL coactivator peptide incubated for 3 hrs by TR-FRET assay
ChEMBL_2266266 Inverse agonist activity at 6His-tagged RORB LBD (unknown origin) expressed in Escherichia coli assessed as inhibition of biotinylated SRC1-2 derived CPSSHSSLTERHKILHRLLQEGSPS-NH2 containing LXXLL coactivator peptide incubated for 3 hrs by TR-FRET assay
Kinase Inhibition Assay A coupled-enzyme assay was used to quantify the ADP generated in the kinase reaction with S6 peptide (RRRLSSLRA) as the phosphoacceptor substrate.
Enzymatic Activity Assay The compounds were tested for serum and glucocorticoid-regulated kinase 1 (SGK-1) inhibitory activity in a substrate phosphorylation assay designed to measure the ability of the isolated enzyme to catalyze the transfer of phosphate from ATP to serine/threonine residues in a fluorescein-labeled substrate peptide, using recombinant human SGK-1 enzyme produced in a baculovirus system (Biomol, Hamburg, Germany, Cat. No. 4-331). The synthesized fluorescent labeled peptide substrate contained (5(6)-Carboxyfluorescein)-RPRAATF-NH2. The phosphorylated substrate peptide and non-phosphorylated substrate peptide were separated with caliper life science's lab-chip technology based on a micro fluidics method. All fluid flow was established on the chip by applying a vacuum of a few psi to the waste well transporting fluid from various sources through interconnecting channels. Because the phosphoryl group is doubly negatively charged, under the pressure-driven hydrodynamic flow.
Fluorescence Assay The promising ligand from the results obtained from ESI-MS assay are subjected to fluorescence in vitro assay. The fluorescence assay takes advantage of the presence of a single tryptophan residue (Trp121) located close to the active site of CypA.
Inhibition Assay Crithidia fasciculata trypanothione reductase (cfTR) was purifed from E.coli using the expression system. The activity of the cfTR was observed from the rate of oxidation of the co-substrate NADPH to NADP+ as measured by a decrease in absorbance at 340nm.
ChEBML_157702 Compound was tested for the inhibition of HIV-1 protease by assaying the cleavage of a fluorescent peptide using HPLC
ChEMBL_28151 (CHEMBL644106) Compound was evaluated for the in vitro inhibition of the Acetylcholinesterase (AChE) from human erythrocytes,
ChEMBL_65474 (CHEMBL677304) Binding ability determined by the displacement of [125I]ET1 from the human endothelin A receptor
Pim Kinase Assay The primary screen and evaluation of the compounds was conducted using an ATP-depletion assay. Recombinant human Pim kinase was incubated with S6 kinase/Rsk-2 peptide 2 in the presence 100 uM of compounds from the screening library (DIVERSet collection of the ChemBridge Corporation). The Kinase-Glo luciferase kit (Promega) was used to measure residual ATP levels after the kinase reaction.
Determination of kinetic parameters and the Ki of effective compounds using the FRET peptide Kinetic parameters were obtained using various concentrations of FRET peptide in the fluorescent assay. The maximal velocity (Vmax) and Michaelis Menten constant (Km) were calculated from the Eadie Hofstee plot. If the type of inhibitionwas found to be competitive using a Lineweaver Burk double reciprocal plot, then the inhibitory constant (Ki) for 3CLpro was estimated using the equation:Ki = IC50/(1+[substrate]/Km).Plots were performed, and kinetic parameters were calculated, using Prism software (Graphpad Software, San Diego, CA).
ChEMBL_1287019 (CHEMBL3111330) Displacement of H3K14(Ac) peptide from TIF1alpha bromodomain (unknown origin) by AlphaScreen assay
ChEMBL_1287021 (CHEMBL3111332) Displacement of H3K14(Ac) peptide from BAZ2B bromodomain (unknown origin) by AlphaScreen assay
ChEMBL_1287022 (CHEMBL3111333) Displacement of H3K56(Ac) peptide from CREBBP bromodomain (unknown origin) by AlphaScreen assay
ChEMBL_1287025 (CHEMBL3111336) Displacement of H4Ac4 peptide from BRD4 bromodomain-1 (unknown origin) by AlphaScreen assay
ChEMBL_1350281 (CHEMBL3267619) Displacement of fluorescent P4 peptide from MDM2 (unknown origin) by fluorescence polarization assay
ChEMBL_2281552 Displacement of fluorescent-labeled BID-BH3 peptide from His-tagged BFL-1 (unknown origin)
ChEMBL_434380 (CHEMBL919858) Displacement of [15I]IMPY from Abeta peptide plaques in Alzheimer's disease patient brain
ChEMBL_439338 (CHEMBL888454) Displacement of FAM-Bim peptide from human Bcl-XL by fluorescence polarization assay
ChEMBL_537289 (CHEMBL985385) Displacement of fluorescein labeled BAD peptide from Bcl-XL by fluorescence polarization assay
ChEMBL_684920 (CHEMBL1286335) Displacement of [125I]peptide YY from NPY2 receptor in human KAN-TS cells
ChEMBL_807446 (CHEMBL1958568) Displacement of acetylated histone peptide from BRD4-BD1 by luminescence proximity homogenous assay
ChEMBL_807447 (CHEMBL1958569) Displacement of acetylated histone peptide from BRD4-BD2 by luminescence proximity homogenous assay
Activity Assay The primary assay for compound inhibitory activity was the ATP depletion assay using the PDKtide substrate purchase from Millipore Corporation.
ChEMBL_63064 (CHEMBL673631) Displacement of the radioligand [3H]spiperone from D2 receptor
Literature assay The assays are from references cited in this article.
Spectrophotometic Assay The IC50 values were obtained from a spectrophotometric assay.
ChEMBL_501393 (CHEMBL1010576) Inhibition of human recombinant Arg235 region of BACE1 by FRET assay
ChEMBL_143828 (CHEMBL748713) Compound was tested for the displacement of [125I]-PYY (SK-N-MC) from Neuropeptide Y receptor type 1 in the membranes prepared from cells
ChEBML_35003 Binding affinity was determined based on the displacement of [125]r-ANF (99-126) from binding sites on bovine adrenal zona glomerulosa cell membranes (Atrionatriuretic peptide receptor B)
ChEMBL_35004 (CHEMBL649027) Binding affinity was determined based on the displacement of [125]r-ANF (99-126) from binding sites on mouse fibroblasts (NIH 3T3) cells (Atrionatriuretic peptide receptor C).
ChEMBL_1776554 (CHEMBL4233546) Binding affinity to human GST-tagged 14-3-3zeta expressed in Escherichia coli assessed as Kd for 14-3-3zeta binding to H+-ATPase peptide motif by isothermal titration calorimetric method
Inhibition Assay Purified recombinant human FGFR3 protein was purchased from Carna Biosciences, Inc. When setting conditions for the measurement of the inhibitory effect of the compounds on FGFR3 kinase activity, a biotinylated peptide (biotin-EEPLYWSFPAKKK) was synthesized for use as a substrate by utilizing the amino acid sequence of FL-Peptide 22 (Caliper Life Sciences, Inc.) with biotin. The purified recombinant human FGFR3 protein used in the test was purchased from Carna Biosciences, Inc. In the measurement of the inhibitory effect of the compounds, first, a test compound was gradually diluted with dimethylsulfoxide (DMSO) to a concentration 20 times higher than the final concentration. Next, the purified human FGFR3 protein, substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 5 mM), ATP (final concentration: 190 .mu.M), and the test compound DMSO solution (final concentration of DMSO: 5%) were added to a reaction buffer.
Inhibition Assay Purified recombinant human FGFR4 protein was purchased from Carna Biosciences, Inc. When setting conditions for the measurement of the inhibitory effect of the compounds on FGFR4 kinase activity, a biotinylated peptide (biotin-EEPLYWSFPAKKK) was synthesized for use as a substrate by utilizing the amino acid sequence of FL-Peptide 22 (Caliper Life Sciences, Inc.) with biotin. The purified recombinant human FGFR4 protein used in the test was purchased from Carna Biosciences, Inc. In the measurement of the inhibitory effect of the compounds, first, a test compound was gradually diluted with dimethylsulfoxide (DMSO) to a concentration 20 times higher than the final concentration. Next, the purified human FGFR4 protein, substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 5 mM), ATP (final concentration: 190 .mu.M), and the test compound DMSO solution (final concentration of DMSO: 5%) were added to a reaction buffer.
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_38359 (CHEMBL651291) In vitro inhibitory activity against Bak-Bh3 peptide binding to the Bcl-2
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.
Surface Plasmon Resonance (SPR) Assay Recombinant full-length hnRNPA1 (aa 1-320) and truncated versions of hnRNPA1, including the N-terminal RNA binding domain (aa 1-196), the middle region (aa 182-268), and the C-terminal region (aa 268-320), were individually covalently coupled to a dextran matrix (CM5 chip) using a Biacore T200 system (GE Healthcare), following the manufacturer's protocols. Immobilized proteins were activated with N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide to form a carbodiamide linkage between carboxyl moieties on the dextran and primary amide groups on the protein. hnRNPA1 variants were dissolved in 10 mM acetate buffer (full-length, pH 4; N-terminal RNA binding domain and the C-terminal region, pH 4.5; middle region, pH 5) to a concentration of 20 μg/ml and flowed over the activated surface for 5 min with PBS. Unreacted groups were blocked with ethanolamine. PBS containing 0.05% (v/v) P20 (surfactant) and 5% DMSO was used for priming and conditioning the surface of the chips. Quercetin was serially diluted (from 200 to 3 μM) in PBS buffer and maintained in DMSO (5% (v/v)) (final concentrations from 10 to 0.15 μM). The baseline response was determined for 120 s (30 μl/min) before perfusing the immobilized proteins with the compounds to allow association to occur. Dissociation was then monitored over a period of an additional 120 s. The immobilized proteins were regenerated with 50 mM NaOH.
ICMT Biochemical Assay An ICMT enzymatic assay was developed using Promega's Methyltransferase-GloTMreagents. In the assay, ICMT catalyzes the methylation of the N-Acetyl-S-farnesyl-L-cysteine by transferring a methyl group from SAM to the farnesylated cysteine and further converts the SAM to SAH. The methyltransferase activity is measured based on the amount of SAH produced from the reaction through the use of coupling enzymes that convert the SAH to ATP. The MTase-Glo detection solution then catalyzes the formation of light from ATP.For the IC50 determination, the compounds were incubated for 30 minutes with 0.04 ug/well ICMT membrane extract from Sf-9 cells. A final concentration of 2.0 μM and 20 μM of SAM and peptide were added and further incubated for 90 minutes at room temperature before adding the MTase Glo and detection reagent. Reaction signals were detected using microplate readers on luminescent mode (Satire Tecan). The IC50 was determined by nonlinear regression, using GraphPad Prism version, 5.03.
ChEBML_58717 Compound was tested for the displacement of [3H]spiperone from Dopamine receptor D2 from rat striatal membranes.
Enzyme Inhibition Assay Stromelysin inhibitory activity is based on the hydrolysis of substance P by recombinant human stromelysin to generate a fragment, substance P 7-11, which can be quantitated by HPLC. The IC50 is calculated from control reaction without the inhibitor. The mean IC50 was obtained from two independent measurements, and the standard deviation of the mean was less than 10%. The mean Ki values reported have been derived from the mean IC50.
ChEMBL_4198 (CHEMBL620000) The compound was tested for the in vitro inhibition of 5-lipoxygenase from the 20000 g supernatant of RBI-1 cells
ChEBML_60687 Displacement of the radioligand [3H]spiperone from the cloned human dopamine receptor D4 expressed in CHO cells
ChEMBL_201273 (CHEMBL804962) Binding affinity against the sigma receptor from guinea pig brain using the radioligand [3H]SKF-10047
ChEMBL_32319 (CHEMBL643512) The compound was evaluated for the binding affinity towards alpha-2 adrenergic receptor from rat cortex
ChEMBL_70660 (CHEMBL678650) The compound was tested for the inhibition of Gamma-amino-N-butyrate transaminase from pig brain
Sigma 1 Assay The test was performed with the radioligand [3H]-(+)-pentazocine (42.5 Ci/mmol) from Perkin Elmer.
ChEMBL_35003 (CHEMBL649026) Binding affinity was determined based on the displacement of [125]r-ANF (99-126) from binding sites on bovine adrenal zona glomerulosa cell membranes (Atrionatriuretic peptide receptor B)
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. Use of 32P-labeled ATP allows this transfer to be monitored by scintillation counting or by autoradiography of the substrate
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. Use of 32P-labeled ATP allows this transfer to be monitored by scintillation counting or by autoradiography of the substrate
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. Use of 32P-labeled ATP allows this transfer to be monitored by scintillation counting or by autoradiography of the substrate.
Kinase Inhibition Assay IC50 is the inhibitor concentration which inhibits 50% of kinase activity that catalyzes the transfer of the terminal phosphate from [gamma-33P] labeled ATP to a protein or peptide substrate. Use of 33P-labeled ATP allows this transfer to be monitored by scintillation counting or by autoradiography of the substrate.
Biochemical Assay Biochemical Assay: The biochemical assay is in a AlphaScreen format. The kinase reaction is based on the IRAK-4 phosphorylation of a biotin labeled peptide. The phosphopeptide is incubated with anti-phosphothreonine antibody as well as streptavidin- and protein A-coated beads. Binding of the protein-A coated beads to the antibody and the streptavidin beads to the peptide, leads to an energy transfer from one bead to the other, ultimately producing a luminescent/fluorescent signal.Generally, the kinase reaction is carried out at 1 nM IRAK4, 1.6 μM peptide, 1 mM ATP in reaction buffer 50 mM Hepes, 60 mM NaCl, 5 mM MgCl2, 0.25 mM MnCl2, 2 mM DTT, 0.01% BSA, 0.01% Tween-20) for 3.5 h at RT.
Biochemical Assay The biochemical assay is in a AlphaScreen format. The kinase reaction is based on the IRAK-4 phosphorylation of a biotin labeled peptide. The phosphopeptide is incubated with anti-phosphothreonine antibody as well as streptavidin- and protein A-coated beads. Binding of the protein-A coated beads to the antibody and the streptavidin beads to the peptide, leads to an energy transfer from one bead to the other, ultimately producing a luminescent/fluorescent signal.Generally, the kinase reaction is carried out at 1 nM IRAK4, 1.6 μM peptide, 1 mM ATP in reaction buffer 50 mM Hepes, 60 mM NaCl, 5 mM MgCl2, 0.25 mM MnCl2, 2 mM DTT, 0.01% BSA, 0.01% Tween-20) for 3.5 h at RT.
Biochemical Assay The biochemical assay is in a AlphaScreen format. The kinase reaction is based on the IRAK-4 phosphorylation of a biotin labeled peptide. The phosphopeptide is incubated with anti-phosphothreonine antibody as well as streptavidin- and protein A-coated beads. Binding of the protein-A coated beads to the antibody and the streptavidin beads to the peptide, leads to an energy transfer from one bead to the other, ultimately producing a luminescent/fluorescent signal.Generally, the kinase reaction is carried out at 1 nM IRAK4, 1.6 μM peptide, 10 μM ATP in reaction buffer 50 mM Hepes, 60 mM NaCl, 5 mM MgCl2, 0.25 mM MnCl2, 2 mM DTT, 0.01% BSA, 0.01% Tween-20) for 3.5 h at RT.
Scintillation Proximity Assay (SPA) The compound inhibitory activity was determined by incubation with purified PLK1 and biotinylated peptide substrate in the presence ATP/[gamma-33P]ATP. After incubation, the phosphorylated substrate was separated from nonincorporated radioactive ATP using SPA beads. Incorporated radioactivity was measured using Packard TopCount.
ChEMBL_1287020 (CHEMBL3111331) Displacement of H3K14(Ac) peptide from PB1-5 bromodomain (unknown origin) by AlphaScreen assay
ChEMBL_1472592 (CHEMBL3417957) Displacement of fluorescent labeled NOXA peptide from recombinant human MCL1 by fluorescence polarization assay
ChEMBL_1748314 (CHEMBL4182824) Displacement of Bax-derived peptide from Bcl-2 (unknown origin) by fluorescence polarization assay
ChEMBL_1748315 (CHEMBL4182825) Displacement of Bad-derived peptide from Bcl-XL (unknown origin) by fluorescence polarization assay
ChEMBL_1813645 (CHEMBL4313219) Displacement of biotinylated H4 peptide from ATAD2B bromodomain (unknown origin) by TR-FRET assay
ChEMBL_2112707 (CHEMBL4821557) Displacement of Bak BH3 domain peptide from human Bax by competitive fluorescence polarization assay
ChEMBL_302256 (CHEMBL829490) Displacement of PRP-1 peptide from mouse Tec kinase SH3 domain by fluorescence polarization
ChEMBL_304472 (CHEMBL832688) Displacement of PRP-1 peptide from human Nck kinase SH3 domain by fluorescence polarization
ChEMBL_304473 (CHEMBL832689) Displacement of PRP-1 peptide from mouse Tec kinase SH3 domain by fluorescence polarization
ChEMBL_304474 (CHEMBL832690) Displacement of PRP-2 peptide from human Hck kinase SH3 domain by fluorescence polarization
ChEMBL_429498 (CHEMBL918621) Displacement of FAM-Bid BH3 peptide from human Mcl1 by FP-based binding assay
ChEMBL_429499 (CHEMBL918622) Displacement of biotinylated Bim BH3 peptide from recombinant His-tagged Mcl1 by ELISA assay
ChEMBL_429500 (CHEMBL918623) Displacement of biotinylated Bim BH3 peptide from recombinant His-tagged Bcl2 by ELISA assay
ChEMBL_441637 (CHEMBL891868) Displacement of Flu-Bak peptide from recombinant antiapoptotic Bcl2 protein by fluorescence polarization assay
ChEMBL_453427 (CHEMBL885426) Displacement of [125]peptide YY from human recombinant Y1 receptor expressed in CHO cells
ChEMBL_500250 (CHEMBL969585) Displacement of fluorescently-tagged BH3 peptide from Bcl-2 by chemiluminescent nitrogen detection method
ChEMBL_500251 (CHEMBL969586) Displacement of fluorescently-tagged BH3 peptide from Bcl-XL by chemiluminescent nitrogen detection method
ChEMBL_593415 (CHEMBL1040543) Displacement of biotin-Ahx-PSpYVNVQN peptide from GST fused Grb2 SH2 domain by ELISA
ChEMBL_610766 (CHEMBL1064401) Displacement of fluorescein-labeled Bak-BH3 peptide from human Mcl1 by fluorescence polarization assay
ChEMBL_613509 (CHEMBL1072275) Displacement of FAM-Bid peptide from human recombinant Bcl-xL by fluorescence polarization assay
ChEMBL_684919 (CHEMBL1286334) Displacement of [125I]peptide YY from NPY1 receptor in human SK-N-MC cells
ChEMBL_306303 (CHEMBL828595) Inhibitory concentration against hepatitis C virus NS4A binding region of NS3 protease
Biochemical Assay In brief, this Rpn11 bioassay employs a fluorescent polarization readout based on the ability of the 26S proteasome to cleave the protein substrate including four tandem ubiquitin proteins fused to a peptide having a unique cysteine labeled with a fluorophore. Cleavage of this substrate by Rpn11 at the junction between the fourth ubiquitin and the peptide, releases the low molecular weight fluorescent peptide. Accordingly, inhibition of fluorescence correlates with inhibition of Rpn11. Inhibition is reported as the half maximal inhibitory concentration (IC50) for the candidate compound.The catalytic JAB1/MPN/Mov34 metalloenzyme (JAMM) motif of Rpn11 is found in 7 different human proteins including the Csn5 subunit of the COP9 signalosome, AMSH, AMSH-LP, the BRCC36 subunit of BRISC, MPND, and MYSM1. All of these enzymes cleave the isopeptide linkage that joins ubiquitin (or the ubiquitin-like protein Nedd8 in the case of Csn5) to a second molecule of ubiquitin or to a substrate. The conserved JAMM domain has the consensus sequence EXnHS/THX7SXXD, in which the histidine (His) and aspartic acid (Asp) residues bind the Zn2+ ion and the fourth coordination site is occupied by a water molecule that is engaged in hydrogen bonding with a conserved glutamic acid (Glu). The Zn2+ acts as a Lewis acid and increases the nucleophilic character of the bound water enough to allow hydrolytic cleavage of the isopeptide bond.
ChEBML_101760 Inhibition of the Collagenase enzyme was determined from purified NSO cells.
ChEBML_102089 Inhibition of the Stromelysin enzyme was determined from purified NSO cells.
ChEBML_140542 Displacement of [3H]glycine from glycine site on the NMDA receptor.
ChEBML_27804 Tested for the ability to inhibit Acetylcholinesterase (AChE) from Torpedo californica
ChEMBL_152918 (CHEMBL758788) Inhibition of phosphodiesterase 3 (PDE3) isolated from the dog aorta
ChEMBL_158991 (CHEMBL763757) Evaluated for inhibition of Protease from the crude plate mixture
ChEMBL_208540 (CHEMBL813634) The binding affinity towards thrombin obtained from human purified enzymes.
ChEMBL_48913 (CHEMBL660743) Concentration required for the inhibition of ACAT from rat gut
ChEMBL_51850 (CHEMBL664073) Inhibition of cruzain, the major cysteine protease from Trypanosoma cruzi
ChEMBL_143850 (CHEMBL747207) Compound was tested for the displacement of [125I]-PYY(3-36) (SK-N-BE2) from Neuropeptide Y receptor type 2 in the membranes prepared from cells
Radiometric Filtration Assay The mTOR activity was determined by measuring the amount of [gamma-33 P] phosphae from ATP incorporated in the substrate protein.
Heme Binding Assay Heme binding was tracked by difference spectroscopy in the Soret region of the UV−visible spectrum. Successive aliquots of 0.5 mM hemin in 0.1 M NaOH were added to both the sample cuvette, which contained 10 μM apo-HutZ, and the referencecuvette. Spectra were recorded 3 min after the addition of each heme aliquot.
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.
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.
Cardiac Myofibril ATPase Assay Following example 15, the counter screen was done using frozen myofibril pellets obtained from cardiac tissue. The assay was done in the same manner as above, with the following notable exceptions: the final well concentration of myofibrils was 1.0 mg/mL and KCl was omitted from the recipe.
ChEMBL_196788 (CHEMBL799731) Inhibitory activity against peptide binding to the Rev Response Element RNA IIB was determined
Protease Inhibition Assay Inhibition constants were determined by a spectrophotometric assay with the chromogenic peptide substrate.
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.
ChEMBL_58484 (CHEMBL670415) Ability to displace [3H]spiperone from D2 dopamine receptor isolated from the striata of male Wistar rats
ChEMBL_58717 (CHEMBL671110) Compound was tested for the displacement of [3H]spiperone from Dopamine receptor D2 from rat striatal membranes.
ChEMBL_61408 (CHEMBL673349) Compound was tested for the displacement of [3H]spiperone from dopamine receptor D2 from rat striatal membranes.
ChEBML_140302 In vitro binding assay for the displacement of [3H]MDL-105519 from the glycine-site of NMDA receptors
ChEBML_60221 Displacement of the radioligand [3H]spiperone from the cloned human Dopamine receptor D2 long expressed in CHO cells
ChEMBL_152935 (CHEMBL757135) Concentration at which 50% of the activity of the Phosphodiesterase 4 from Human U937 cells is inhibited
ChEMBL_63674 (CHEMBL670477) Binding ability determined by the displacement of [125 I]ET-3 from the human Endothelin B receptor
Enzymatic Assay The enzymatic activity of PAK4 KD was measured by its ability to catalyzed the transfer of a phosphate residue from a nucleoside triphosphate to an amino acid side chain of a commercially available peptide (amino acid sequence EVPRRKSLVGTPYWM).
Radioligand Binding Assay IC50 values for test compounds were determined from nonlinear regression analysis of data collected from ligand binding experiments. The inhibition constant (Ki) was calculated from IC50 value by the Cheng and Prusoff equation.
Inhibition Assay The PPlase activity of recombinant CypA or D, produced by thrombin cleavage of GST-CypA or D, was determined by following the rate of hydrolysis of N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide by chymotrypsin. Chymotrypsin only hydrolyzes the trans form of the peptide, and hydrolysis of the cis form, the concentration of which is maximized by using a stock dissolved in trifluoroethanol containing 470 mM LiCl, is limited by the rate of cis-trans isomerization. CypA or D was equilibrated for 1 h at 5° C. with selected test article using a drug concentration range from 0.1 to 20 nM. The reaction was started by addition of the peptide, and the change in absorbance was monitored spectrophotometrically at 10 data points per second. The blank rates of hydrolysis (in the absence of CypA or D) were subtracted from the rates in the presence of CypA or D.
Fluorimetric Assay The MMP assay were performed evaluating the ability of compounds 1a-6a and 1b-6b to prevent the hydrolysis of the fluorescence-quenched peptide substrate Mca-Pro-Gly-Leu-Dpa-ala-Arg-NH2.
FRET Assay for LRH-1 The screen utilizes a ligand mediated co-factor interaction between purified bacterial expressed ligand binding domain of human LRH1 and a TIF2-derived peptide. Detection of the associated complex was measured by time resolved fluorescence energy transfer (TR-FRET). The EC50s of the test compound was estimated from a plot using the ratio of fluorescence values collected at 671 nm to fluorescence values collected 618 nm versus concentration of test compound added. Test compounds (agonists) that increased the affinity of the receptors for the peptide yielded an increase in fluorescent signal.
TR-FRET Assay Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyze mono- and symmetric demethylation on arginine residues of histone or non-histone proteins in presence of S-adenosylmethionine (AdoMet or SAM) a cofactor responsible for donating the methyl group. PRMT5 is reported to be overexpressed in several human cancers. To identify compounds that inhibit the PRMT5 and decrease its activity, a TR-FRET based assay has been established. Time-resolved fluorescence resonance energy transfer (TR-FRET) HTS assays are homogeneous proximity assays where the interaction of two dye-labeled binding partners is detected by the energy transfer between a donor and an acceptor dye, and the subsequent light emission by the acceptor dye. PRMT5 catalyzes Histone H4 peptide [1-16] which is biotin tagged to the Lysine amino acid at carboxyl end, in presence of S-adenosyl-1-methionine (SAM) to methylate the peptide. The antibody specific to mono methylated H4 peptide (H4R3) with Ig conjugate binds to the methylated peptide, indirectly binding to the Europium lanthanide. SureLight Allophycocyanin-Streptavidin binds to the biotin tag of the peptide, therefore accepting the energy transferred from the Europium lanthanide. This energy transfer between Europium to SureLight Allophycocyanin is a direct measure of the activity/inhibition of the PRMT5 enzyme.
Scintillation Proximity Assay (SPA) The compound inhibitory activity was determined by incubation with purified PLK enzyme and biotinylated peptide substrate in the presence ATP/[gamma-33P]ATP. After incubation, the phosphorylated substrate was separated from nonincorporated radioactive ATP using SPA beads. Incorporated radioactivity was measured using Packard TopCount.
ChEBML_49899 Tested for the 50% displacement of [125I]CCK-8 from membrane preparation isolated from CHO-K1 cells stably transfected with the cDNA of human Cholecystokinin type A receptor
Peptidyl Prolyl Isomerase (PPIase) Inibition Assay PPIase(Rotamase) activity of FKBP12 was assayed using the peptide N-succinyl Ala-Leu-Pro-Phe p-nitroanilide as substrate. It is based on the observation that chymotrypsin cleaves the C-terminal amide bond only in the trans conformer of the chromogenic substrate. The rapid hydrolysis perturbs the cis-trans conformational equilibrium, which allows one to monitor the PPIase-catalyzed cis-to-trans isomerization. The absorbance at 390 nM versus time was monitored for up to 400 s. Rate constants were generated from the absorbance versus time plots at 8-12 compound concentrations. The Kiapp was determined from the corrected rate constants using an IC50 equation or a tight-binding equation by Morrison.
Ray2010 Assay 74 Table S2 shows raw Ki data for the current study combined with data collected from the literature for the ten additional compounds.
ChEMBL_799260 (CHEMBL1941810) Noncompetitive inhibition of human full length recombinant MMP13 using triple-helical fTHP-15 as substrate by Lineweaver-Burk plot analysis
ChEMBL_799327 (CHEMBL1941964) Inhibition of MMP1 expressed in Escherichia coli using triple-helical fTHP-15 as substrate after 4 hrs by FRET assay
Enzymatic Activity Assay The compounds were tested for serum and glucocorticoid-regulated kinase 1 (SGK-1) inhibitory activity in a substrate phosphorylation assay designed to measure the ability of the isolated enzyme to catalyze the transfer of phosphate from ATP to serine/threonine residues in a fluorescein-labeled substrate peptide, using recombinant human SGK-1 enzyme produced in a baculovirus system (Biomol, Hamburg, Germany, Cat. No. 4-331). The synthesized fluorescent labeled peptide substrate contained (5(6)-Carboxyfluorescein)-RPRAATF-NH2. The phosphorylated substrate peptide and non-phosphorylated substrate peptide were separated with caliper life science's lab-chip technology based on a micro fluidics method. All fluid flow was established on the chip by applying a vacuum of a few psi to the waste well transporting fluid from various sources through interconnecting channels. Because the phosphoryl group is doubly negatively charged, under the pressure-driven hydrodynamic flow and the voltage-driven flow within the electric field, the fluorescent labeled peptide substrate and its phosphorylation product appear at different times in the detection window to the detection point. Substrate turnover can thus be determined as the ratio of the product peak area and the sum of substrate peak area and product peak area.The enzyme reaction was carried out in a buffer containing 25 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 2 mM MnCl2, 2 mM DTT, and 0.03% bovine serum albumine. The enzyme was pre-incubated with the test compound for 30 min at 24° C. The kinase reaction was initiated by addition of the substrate mixture containing the peptide substrate (final concentration 1 μM) and ATP (final concentration 10 μM). After 60 min incubation at 37° C., the enzyme reaction was terminated by adding a buffer containing 100 mM Hepes (pH 7.4) and 35 mM EDTA.
Enzyme Assay The inhibitory activity of compounds against AURKA, AURKB, JAK1, JAK2 and JAK3 was determined in Z′-LYTE assays run by ThermoFisher Scientific as part of their SelectScreen Biochemical Kinase Profiling Service. The Z′-LYTE biochemical assay format employs a fluorescence-based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage. The peptide substrate is labeled with two fluorophores one at each end that make up a FRET pair. In the primary reaction, the kinase transfers the gamma-phosphate of ATP to a single tyrosine, serine or threonine residue in a synthetic FRET-peptide. In the secondary reaction, a site-specific protease recognises and cleaves non-phosphorylated FRET-peptides. Phosphorylation of FRET-peptides suppresses cleavage by the Development Reagent. Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor (i.e., fluorescein) fluorophore on the FRET-peptide, whereas uncleaved, phosphorylated FRET-peptides maintain FRET. A ratiometric method, which calculates the ratio (the Emission Ratio) of donor emission to acceptor emission after excitation of the donor fluorophore at 400 nm, is used to quantitate reaction progress. Both cleaved and uncleaved FRET-peptides contribute to the fluorescence signals and therefore to the Emission Ratio. The extent of phosphorylation of the FRET-peptide can be calculated from the Emission Ratio. The Emission Ratio will remain low if the FRET-peptide is phosphorylated (i.e., no kinase inhibition) and will be high if the FRET-peptide is non-phosphorylated (i.e., kinase inhibition).
Isothermal Titration Calorimetry Studies of STAT3 Binding The binding isotherm from the integrated thermogram fit using the one-site model in the PEAQ-ITC software generated from the titration of Compound 1 into purified STAT3 show KD of 880 nM. The signature plot show the thermodynamics parameters for the titration reveals ΔH=−21.1 kJ/mol, ΔG=−34.6 kJ/mol, and −TΔS=−13.2 kJ/mol.
ChEBML_1711442 Displacement of [125I]peptide YY from human Y1 receptor after 120 mins by scintillation counting analysis
ChEBML_1711443 Displacement of [125I]peptide YY from human Y2 receptor after 120 mins by scintillation counting analysis
ChEMBL_1460643 (CHEMBL3395884) Inhibition of DNA-PK purified from HeLa nuclear extracts assessed as EPPLSQEAFADLWKKR peptide substrate phosphorylation
ChEMBL_1767769 (CHEMBL4219881) Displacement of FAM-labeled HIF-1alpha peptide from VBC (unknown origin) by fluorescence polarization assay
ChEMBL_1833236 (CHEMBL4333244) Displacement of fluorescence-labelled Ac-ARA peptide from WDR5 (unknown origin) by fluorescence polarization assay
ChEMBL_2074780 (CHEMBL4730314) Displacement of FAM-labeled HIF-1alpha peptide from VCB (unknown origin) by fluorescence polarization assay
ChEMBL_2230035 (CHEMBL5143807) Displacement of CPSF6 peptide from HIV1 capsid protein by surface plasmon resonance-based competition assay
ChEMBL_2230036 (CHEMBL5143808) Displacement of NUP153 peptide from HIV1 capsid protein by surface plasmon resonance-based competition assay
ChEMBL_429496 (CHEMBL918619) Displacement of FAM-Bid BH3 peptide from human recombinant Bcl2 by FP-based binding assay
ChEMBL_429497 (CHEMBL918620) Displacement of FAM-Bak BH3 peptide from human Bcl-xL by FP-based binding assay
ChEMBL_441639 (CHEMBL891870) Displacement of Flu-Bak peptide from recombinant antiapoptotic Bcl-w protein by fluorescence polarization assay
ChEMBL_610765 (CHEMBL1064400) Displacement of fluorescein-labeled Bak-BH3 peptide from human Bcl-XL by fluorescence polarization assay
ChEMBL_643624 (CHEMBL1212488) Displacement of [125I]peptide YY from human recombinant Y1 receptor expressed in SK-NM- cell
ChEMBL_643625 (CHEMBL1212489) Displacement of [125I]peptide YY from human recombinant Y2 receptor expressed in KAN-TS cells
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).
CB Receptor Binding Assay IC50 values for test compounds were determined from nonlinear regression analysis of data collected from ligand binding experiments. The inhibition constant (Ki) was calculated from IC50 value by the Cheng and Prusoff equation.
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.
Biochemical Activity Assay for BRD4 1) using BRD4-BD1 protein and BRD4-BD2 protein from BPS company for the experiments; as well as polypeptides from ANASPEC company; detection reagents from Perkinelmer company;2) screening compounds by applying the experimental principle of TR-FRET;3) testing the compounds.
Radioligand Displacement Assay The receptor-binding assay was conducted using [3H]4-hydroxytamoxifen (4-OHT) as the radioligand. To estimate the binding affinity, the IC50 values (the concentrations for the half-maximal inhibition) were calculated from the dose-response curves by using the nonlinear analysis program ALLFIT.
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.
ChEMBL_142637 (CHEMBL746905) Binding affinity for Norepinephrine transporter is assessed from the ability to displace [3H]nisoxetine from rat frontal cortex
ChEMBL_200909 (CHEMBL880920) Inhibitory concentration bound to tryptophan containing region of Serum albumin in fluorescence quenching
Fluorescence Polarization Assay A fluorescence polarization (FP) assay monitor the fluorescein-labeled C-terminal Hsp90 peptide-TPRA interaction. FP assay will also confirm binding interaction between hit compounds identified from AlphaScreen assay.
ChEBML_75879 The inhibitory activity was measured for the supercoiling activity of DNA gyrase isolated from Escherichia coli K-12 C600.
ChEMBL_139910 (CHEMBL746846) Allosteric potency against the dissociation of radioligand [3H]N-methylscopolamine from the porcine cardiac Muscarinic acetylcholine receptor M2
ChEMBL_140072 (CHEMBL747450) Displacement of [3H]-OXO-M (oxotremorine-M) from the central muscarinic receptor sites of the rat brain membranes
ChEMBL_32315 (CHEMBL646332) The ability to displace [3H]clonidine from the Alpha-2 adrenergic receptor was determined in rat brain membrane
ChEMBL_33508 (CHEMBL647005) The compound's binding affinity against Alpha-2B adrenergic receptor from rat kidney homogenate in the presence of phentolamine
BACE Assay For each compound being tested, the BACE activity was monitored in a fluorescence quenching assay (FRET) using the ectodomain of BACE (aa 1-454) fused to a myc-his tag and secreted from HEK293/BACEect. cells into OptiMEM (Invitrogen) as enzyme source and a substrate peptide derived from the APP-Swedish mutation which possesses a Cy3-fluorophore at the N-terminus and a Cy5Q-quencher at the C-terminus (Cy3-SEVNLDAEFK-Cy5Q-NH2; Amersham).
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Using human recombinant KRAS G12D, SOS and c-Raf proteins, the inhibitory activity of subject compounds on the complex formation of the proteins was examined by a time-resolved fluorescence resonance energy transfer (TR-FRET) method.Biotinylated AviTag-KRAS G12D (amino acid region of 1-185, GDP) (2.5 μL; 400 nM) and subject compounds dissolved in an assay buffer (50 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween 20, pH 7.0) were added to a 384-well plate (from Corning) in a liquid volume of 2.5 μL at 40,000 nM to 40 nM. Son of Sevenless (SOS) (amino acid region of 564-1049, 2.5 μL; 1.3 μM) and c-Raf (amino acid region of 51-131) GST (2.5 μL; 130 nM) containing GTP (from Sigma-Aldrich; 2 μM) were added to the plate, and the plate was allowed to stand for 1 hour at room temperature. Then, a mixture liquid (10 μL) of LANCE Ulight-anti-GST (from PerkinElmer; 120 nM) and LANCE Eu-W1024 labeled Streptoavidin (from PerkinElmer; 100 ng/mL) was added, and the 620-nm and 665-nm fluorescence intensities were measured using EnVision 2104 (from PerkinElmer) under the conditions of an excitation wavelength of 337 nm. After standardizing the values with the fluorescence intensity at a reference wavelength of 620 nm, the 50% inhibitory concentrations (IC50) were calculated by Sigmoid-Emax model nonlinear regression analysis with the signaling value in treatment with the solvent taken as 0% inhibition and with the signaling value without the addition of GTP taken as 100% inhibition.
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.

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