carbocysteine (R)-S-(carboxymethyl)cysteine (2R)-2-amino-3-[(carboxymethyl)sulfanyl]propanoic acidS-(carboxymethyl)-L-cysteine BDBM50213735 CHEMBL396416 S-(carboxymethyl)-(R)-cysteine S-carboxymethyl-L-cysteine (L)-2-Amino-3-(carboxymethylthio)propionic acid L-3-((carboxymethyl)thio)alanine
leukotriene E4 (5S-(5R*,6S*(S*),7E,9E,11Z,14Z))-6-((2-Amino-2-carboxyethyl)thio)-5-hydroxy-7,9,11,14-eicosatetraenoic acid BDBM50297387 LTE4 CHEMBL509456 5S-hydroxy,6R-(S-cysteinyl),7E,9E,11Z,14Z-eicosatetraenoic acid (5S,6R,7E,9E,11Z,14Z)-6-(cystein-S-yl)-5-hydroxyicosa-7,9,11,14-tetraenoic acidS-{(1R,2E,4E,6Z,9Z)-1-[(1S)-4-carboxy-1-hydroxybutyl]pentadeca-2,4,6,9-tetraen-1-yl}-L-cysteine
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- ChEBML_41854 In vitro for inhibition of [14C]taurocholate uptake in baby hamster kidney cells transfected with the cDNA of human Bile acid transporter (H14 cells)
- Inhibition Assay Inhibition of HIV-protease activity for selected acids at P3-P3' positions.
- ChEBML_35875 In vitro inhibitory activity against uptake of [14C]taurocholate in baby hamster kidney cells transfected with cDNA from human Apical Sodium-Codependent Bile Acid Transporter
- ChEMBL_1933900 (CHEMBL4479552) Inhibition of human recombinant DOT1L (1 to 420 amino acids) expressed in Escherichia coli
- ChEMBL_559411 (CHEMBL1017265) Inhibition of histidine-tagged ACK1 (amino acids 117 to 489) expressed in SF9 cells
- ChEMBL_790766 (CHEMBL1926219) Inhibition of recombinant human AKT1 using GSK3 (amino acids 14 to 27) as substrate
- ChEMBL_820572 (CHEMBL2040309) Inhibition of human N-myristoyltransferase 1 using human pp60Src92-16 amino acids) as substrate
- ChEMBL_820573 (CHEMBL2040310) Inhibition of human N-myristoyltransferase 2 using human pp60Src92-16 amino acids) as substrate
- ChEMBL_967551 (CHEMBL2398945) Inhibition of wild type GST-tagged LRRK2 ((1326 to 2517 amino acids) (unknown origin)
- ChEMBL_1910044 (CHEMBL4412490) Inhibition of N-terminal His-tagged human TAK1 (1 to 303 amino acids)/human TAB1 (437 to 504 amino acids) expressed in baculovirus expression system using fluorescence-labeled substrate by off-chip mobility shift assay
- ChEMBL_1285739 (CHEMBL3107728) Inhibition of Clostridium botulinum BoNT/A light chain (1 to 425 amino acids) by FRET method
- ChEMBL_2170548 (CHEMBL5055607) Inhibition of C-terminal His-tagged WNV NSB2 (52 to 96 amino acids)-NS3 (1 to 184 amino acids) protease expressed in Escherichia coli BL21(DE3) using Boc-GRK-AMC as substrate measured by flourescence based plate reader assay
- Glycocholic acid Uptake Radiometric Assay ISBT Hu HEK Uptake SPA 13203 IBAT HUM Ileal Bile Acid Transporter Human HEK Glycocholic acid Uptake Radiometric SPA Inhibitor IC50 Mean IC50 (nM) was determined.
- ChEMBL_1285740 (CHEMBL3107729) Inhibition of Clostridium botulinum BoNT/A light chain (1 to 425 amino acids) by LC-MS analysis
- ChEMBL_787631 (CHEMBL1918084) Binding affinity to recombinant rat brain PLCdelta1 PH domain (amino acids 11 to 140) by SPR analysis
- ChEMBL_787632 (CHEMBL1918085) Binding affinity to recombinant rat brain Grp1 PH domain (amino acids 1 to 120) by SPR analysis
- ChEMBL_2170549 (CHEMBL5055608) Competitive inhibition of C-terminal His-tagged WNV NSB2 (52 to 96 amino acids)-NS3 (1 to 184 amino acids) protease expressed in Escherichia coli BL21(DE3) using Boc-GRK-AMC as substrate measured by flourescence based plate reader assay
- ChEMBL_863095 (CHEMBL2175491) Competitive inhibition of N-terminal His6-tagged recombinant human c-MET (974 to 1390 amino acids) by spectrophotometry
- ChEMBL_966836 (CHEMBL2400837) Binding affinity to substance P receptor (1 to 7 amino acids) binding site in rat spinal cord membranes
- ChEMBL_2238135 (CHEMBL5152031) Inhibition of human recombinant PARP5a (E1023 to T1327 amino acids) incubated for 4 hrs by fluorescence anisotropy binding assay
- ChEMBL_2333315 Inhibition of GST-fused G9a (amino acids 685 to 1000) (unknown origin) expressed in Escherichia coli BL21 by DELFIA assay
- ChEMBL_2333316 Inhibition of GST-fused GLP (amino acids 610 to 917) (unknown origin) expressed in Escherichia coli BL21 by DELFIA assay
- ChEMBL_968095 (CHEMBL2401547) Binding affinity to MDM2 (25 to 109 amino acids) (unknown origin) after 30 mins by surface plasmon resosnance analysis
- ChEMBL_1578159 (CHEMBL3807172) Inhibition of recombinant LSD1 (157 to 852 amino acids) (unknown origin) expressed in Escherichia coli BL21(DE) using H3K4me2 substrate
- ChEMBL_1788619 (CHEMBL4260353) Agonist activity at human LXRalpha-LBD (182 to 447 amino acids) expressed in HEK293T cells by luciferase reporter gene assay
- ChEMBL_1788620 (CHEMBL4260354) Agonist activity at human LXRbeta-LBD (196 to 461 amino acids) expressed in HEK293T cells by luciferase reporter gene assay
- ChEMBL_864591 (CHEMBL2176640) Inhibition of human BACE1 (43-454 amino acids) expressed in Escherichia coli BL21 using SEVNLDAEFRHDSGYEK-biotinafter 3 hrs by ELISA
- ChEMBL_935054 (CHEMBL2320919) Inhibition of human HER2 cytoplasmic domain (amino acids 676 to 1245) expressed in Sf9 cells by DELFIA time resolved fluorometry
- ChEMBL_968766 (CHEMBL2399319) Inhibition of full-length human KRas4B (amino acids 1 to 188)-SOS interaction assessed as inhibition of nucleotide exchange activity
- ChEMBL_2170550 (CHEMBL5055609) Inhibition of C-terminal His-tagged ZIKV NSB2 (52 to 96 amino acids)-NS3 (1 to 184 amino acids) protease expressed in Escherichia coli BL21(DE3) preincubated for 10 mins followed by addition of Boc-GKR-AMC substrate and measured by flourescence based plate reader assay
- ChEMBL_2170551 (CHEMBL5055610) Competitive inhibition of C-terminal His-tagged ZIKV NSB2 (52 to 96 amino acids)-NS3 (1 to 184 amino acids) protease expressed in Escherichia coli BL21(DE3) preincubated for 10 mins followed by addition of Boc-GKR-AMC substrate and measured by flourescence based plate reader assay
- ChEMBL_1331153 (CHEMBL3226853) Reversible inhibition of recombinant LSD1 catalytic domain (178 to 831 amino acids) (unknown origin) expressed in baculovirus infected insect Sf9 cells
- ChEMBL_771323 (CHEMBL1839595) Inhibition of human FAS assessed as synthesis of long chain fatty acids from malonyl CoA after 60 mins by fluorescence assay
- ChEMBL_787633 (CHEMBL1918086) Binding affinity to recombinant rat brain Grp1 PH domain (amino acids 1 to 120) after 10 mins by pull-down assay
- ChEMBL_961840 (CHEMBL2390132) Inhibition of human recombinant PDE4B (152 to 564 amino acids) using cAMP as substrate after 30 mins by plate reader analysis
- ChEMBL_968096 (CHEMBL2398954) Inhibition of TMRA-p53 binding to MDM2 (25 to 109 amino acids) (unknown origin) after 30 mins by fluorescence polarization assay
- Determination of Compound's ROCK Inhibitory Activity In Vitro (Z'Lyte Assay) Recombinant ROCK1 (amino acids 1-535) and ROCK2 (amino acids 1-552) proteins were purchased from ThermoFisher Scientific. Compound's activities were measured by Z′-lyte kinase kit (ThermoFisher Scientific) and IC50 was calculated
- ChEMBL_1296166 (CHEMBL3132000) Inhibition of Mycobacterium tuberculosis full length biotinylated InhA (270 amino acids) using DDCoA as substrate assessed as NADH oxidation by fluorimetric analysis
- ChEMBL_1331154 (CHEMBL3226854) Time-dependent inhibition of recombinant LSD1 catalytic domain (178 to 831 amino acids) (unknown origin) expressed in baculovirus infected insect Sf9 cells
- ChEMBL_1456579 (CHEMBL3369961) Inhibition of human PDE10A (amino acids 14 to 779) using [3H]-labelled cyclic nucleotide as substrate after 1 hr b beta counting
- ChEMBL_1931157 (CHEMBL4434408) Inhibition of human recombinant GST tagged JAK3 kinase domain (781 to 1124 amino acids) expressed in insect cells in presence of ATP
- ChEMBL_2057037 (CHEMBL4712038) Inhibition of recombinant SHP2 (262 to 532 amino acids) (unknown origin) incubated for 1 hr using 20 uM DiFMUP by DiFMUP assay
- ChEMBL_2057038 (CHEMBL4712039) Inhibition of recombinant SHP2 (262 to 532 amino acids) (unknown origin) incubated for 1 hr using 10 uM DiFMUP by DiFMUP assay
- ChEMBL_944555 (CHEMBL2339071) Binding affinity to recombinant His-tagged Grb10 interacting GYF protein 2 (745-1030 amino acids) (unknown origin) by surface plasmon resonance analysis
- ChEMBL_953654 (CHEMBL2352558) Inhibition of wild type GST-tagged LRRK2 (970-2527 amino acids)(unknown origin) assessed as inhibition of LRRKtide phosphorylation by HTRF assay
- ChEMBL_968765 (CHEMBL2399318) Inhibition of full-length human KRas4B (amino acids 1 to 188)-SOS interaction assessed as inhibition of SOS-mediated nucleotide release activity
- ChEMBL_985355 (CHEMBL2432164) Inhibition of recombinant GST-tagged FAK catalytic domain region (amino acids 411-686) (unknown origin) expressed in Sf9 cells after 5 mins
- Pharmaceutical Effect Mean Inhibitory Effect ISBT Hu HEK Uptake SPA 13203 IBAT HUM Ileal Bile Acid Transporter Human HEK Glycocholic acid Uptake Radiometric SPA Inhibitor IC50 Mean IC50 (nM) was determined for the compounds of examples 1-14.
- ChEMBL_1879629 (CHEMBL4381023) Inhibition GST-tagged recombinant HRAS G12V mutant (1 to 166 amino acids) (unknown origin) expressed in Escherichia coli C41(DE3) by SPR assay
- ChEMBL_1898487 (CHEMBL4400602) Inhibition of N-terminal GST-fused human FGFR1 cytoplasmic domain (398 to 822(end) amino acids) using CSKtide substrate incubated for 90 mins
- ChEMBL_1898488 (CHEMBL4400603) Inhibition of N-terminal GST-fused human FGFR2 cytoplasmic domain (399 to 821(end) amino acids) using CSKtide substrate incubated for 90 mins
- ChEMBL_1898489 (CHEMBL4400604) Inhibition of N-terminal GST-fused human FGFR3 cytoplasmic domain (436 to 806(end) amino acids) using CSKtide substrate incubated for 90 mins
- ChEMBL_1898490 (CHEMBL4400605) Inhibition of N-terminal GST-fused human FGFR4 cytoplasmic domain (460 to 802(end) amino acids) using CSKtide substrate incubated for 90 mins
- ChEMBL_2122326 (CHEMBL4831473) Inhibition of ACSS2 in human HCT-15 cells assessed as inhibition of 14C acetate incorporation into fatty acids by microbeta scintillation counting analysis
- ChEMBL_2585389 Binding affinity to human recombinant PYK2 (amino acids 420-691) expressed in Escherichia coli, BL21 (DE3) assessed as equilibrium dissociation constant by SPR assay
- ChEMBL_773166 (CHEMBL1838642) Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis
- ChEMBL_973989 (CHEMBL2410314) Competitive inhibition of N-terminal GST-tagged human PLK4 (1 to 391 amino acids) expressed in Escherichia coli in the presence of ATP
- ChEMBL_1336210 (CHEMBL3241458) Binding affinity to recombinant human RPA70 A/B region (181 to 422 amino acids) expressed in Escherichia coli Rosetta by fluorescence polarization anisotropy assay
- ChEMBL_1444239 (CHEMBL3380178) Inhibition of N-terminal GST-fused full-length human IRAK4 (1 to 460 amino acids) assessed as reduction in phosphorylated substrates by Caliper assay
- ChEMBL_1557232 (CHEMBL3773607) Inhibition of GST-tagged human SIRT1 (133 to 747 amino acids) using ZMAL as substrate after 4 hrs by fluorescence-based microplate reader method
- ChEMBL_1855685 (CHEMBL4356414) Inhibition of human full-length USP7 (1 to 1102 amino acids) expressed in Escherichia coli BL21(DE3) incubated 30 mins by Ubiquitin-AMC assay
- ChEMBL_1898483 (CHEMBL4400598) Inhibition of N-terminal GST-tagged recombinant human FGFR1 (456 to 765 amino acids) incubated for 60 mins by time-resolved fluorescence kinase assay
- ChEMBL_2585379 Inhibition of purified-activated FAK kinase domain (amino acids 410-689) (unknown origin) using Glu and Tyr, p(Glu/Tyr) peptide in presence of ATP
- ChEMBL_1885551 (CHEMBL4387133) Inhibition of human full length GST-tagged CDK4 (1 to 303(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay
- ChEMBL_1885552 (CHEMBL4387134) Inhibition of human full length GST-tagged CDK6 (1 to 326(end) amino acids)/Cyclin D3 (1 to 292(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay
- ChEMBL_1885555 (CHEMBL4387137) Inhibition of human full length GST-tagged CDK2 (1 to 298(end) amino acids)/Cyclin E1 (1 to 410(end) amino acids) expressed in baculovirus expression system assessed as inhibition constant using Ulight-4E-BP1 as substrate preincubated for 30 mins followed by substrate addition and incubated for 90 mins by TR-FRET assay
- ChEMBL_1336033 (CHEMBL3240326) Inhibition of GST-fused human FLT3 cytoplasmic domain (amino acids 564 to 993) using Ulight-JAK1 as substrate after 1 hr by TR-FRET assay
- ChEMBL_1336209 (CHEMBL3241316) Binding affinity to recombinant human RPA70 N-terminal domain (1 to 120 amino acids) expressed in Escherichia coli BL21-DE3 by fluorescence polarization anisotropy assay
- ChEMBL_1337212 (CHEMBL3240620) Inhibition of autophosphorylation of EGFR cytoplasmic domain (amino acids 645 to 1186) (unknown origin) expressed in Sf9 cells after 1 hr by time-resolved fluorometry
- ChEMBL_1459715 (CHEMBL3370433) Binding affinity to N-terminal His6-tagged pVHL (54 to 213 amino acids) (unknown origin) expressed in Escherichia coli BL21 (DE3) by isothermal titration calorimetry
- ChEMBL_1619578 (CHEMBL3861747) Inhibition of N-terminal GST tagged human TrkC catalytic domain (456 to 825 amino acids) using fluorescence-labeled substrate by off-chip mobility shift assay
- ChEMBL_876373 (CHEMBL2186306) Inhibition of human recombinant mTOR (1360 to 2549 amino acids) assessed as reduction in phosphorylation of (GFP)-4-EBP1 after 30 mins by FRET assay
- ChEMBL_1337213 (CHEMBL3240621) Inhibition of autophosphorylation of human HER2 cytoplasmic domain (amino acids 676 to 1245) (unknown origin) expressed in Sf9 cells after 1 hr by time-resolved fluorometry
- ChEMBL_1499595 (CHEMBL3584541) Inhibition of N-terminal His6-tagged human recombinant PAK4 (300 to 591 amino acids) using peptide-7 substrate by pyruvate kinase and lactate dehydrogenase coupled assay
- ChEMBL_1557218 (CHEMBL3773441) Inhibition of N-terminal his6-tagged human SIRT2 (25 to 389 amino acids) using ZMAL as substrate after 4 hrs by fluorescence-based microplate reader method
- ChEMBL_2020129 (CHEMBL4673942) Inhibition of N-terminal Flag tagged- human HDAC10 (2 to 631 amino acids) expressed in baculovirus infected Sf9 cells using Fluor deLys substrate by fluorescence method
- ChEMBL_967970 (CHEMBL2401074) Binding affinity to recombinant human His-tagged MDM2 (1 to 118 amino acids) using p53-based PMDM6-F as probe after 15 mins by competition assay
- ChEMBL_1281650 (CHEMBL3102587) Inhibition of JNK3 (39 to 402 amino acids) (unknown origin) expressed in Escherichia coli BL21(DE3) using biotinylated ATF2 as substrate after 15 mins by HTRF assay
- ChEMBL_1453489 (CHEMBL3362176) Inhibition of human PDE4D2 catalytic domain (86 to 413 amino acids) expressed in Escherichia coli strain BL21 after 15 mins using [3H]-cAMP by liquid scintillation counting
- ChEMBL_1453676 (CHEMBL3363782) Inhibition of human recombinant N-terminal Avi-tagged glutamate carboxypeptidase 2 extracellular domain (44 to 750 amino acids) using pteroyl-di-L-glutamate substrate by HPLC method
- ChEMBL_1499749 (CHEMBL3585198) Inhibition of PKAalpha (1 to 351 amino acids) (unknown origin) using Leu-Arg-Arg-Ala-Ser-Leu-Gly as substrate by pyruvate kinase/lactate dehydrogenase coupled assay
- ChEMBL_1672604 (CHEMBL4022633) Inhibition of N-terminal GST fused human recombinant JAK1 (866 to 1154 amino acids) expressed in insect cells using ATP and peptide substrate (FITC-C6-KKHTDDGYMPMSPGVA-NH2
- ChEMBL_1672605 (CHEMBL4022634) Inhibition of N-terminal GST fused recombinant JAK2 (831 to 1132 amino acids) (unknown origin) expressed in insect cells using ATP and peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2
- ChEMBL_1672607 (CHEMBL4022636) Inhibition of N-terminal GST fused recombinant JAK3 (781 to 1124 amino acids) (unknown origin) expressed in insect cells using ATP and peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2
- ChEMBL_1759898 (CHEMBL4194906) Binding affinity to BRD4 bromodomain 1 (K57 to E168 amino acids) (unknown origin) using Alexa647-labeled BET-inhibitor as fluorescent probe by bromodomain TR-FRET binding assay
- ChEMBL_1759899 (CHEMBL4194907) Binding affinity to BRD4 bromodomain 2 (E352 to M457 amino acids) (unknown origin) using Alexa647-labeled BET-inhibitor as fluorescent probe by bromodomain TR-FRET binding assay
- ChEMBL_934773 (CHEMBL2318907) Inhibition of EGFR cytoplasmic domain (amino acids 645 to 1186) (unknown origin) expressed in Sf9 cells assessed as reduction in enzyme autophosphorylation by DELFIA time resolved fluorometry
- ChEMBL_965919 (CHEMBL2394350) Inhibition of human recombinant CLK3 (275 to 632 amino acids) expressed in Escherichia coli BL21(DE3) preincubated for 10 mins prior to substrate addition by LDH assay
- ChEMBL_1280886 (CHEMBL3095184) Inhibition of human endothelial lipase using HDL as substrate assessed as release of free fatty acids preincubated for 30 mins followed by substrate addition measured after 2 hrs
- ChEMBL_1759900 (CHEMBL4194908) Binding affinity to BRDT bromodomain 1 to 2 (N21to P380 amino acids) (unknown origin) using Alexa647-labeled BET-inhibitor as fluorescent probe by bromodomain TR-FRET binding assay
- ChEMBL_1812686 (CHEMBL4312260) Inhibition of recombinant human N-terminal FLAG-tagged mTOR (1362 to end amino acids) using ULight-4E-BP1 as substrate incubated for 1 hr by LANCE Ultra assay
- ChEMBL_2081810 (CHEMBL4737601) Inhibition of recombinant human N-terminal FLAG-tagged mTOR (1362 to end amino acids) using ULight-4E-BP1 as substrate incubated for 1 hr by LANCE Ultra assay
- ChEMBL_794139 (CHEMBL1931877) Inhibition of human recombinant BACE1 ectodomain (1 to 460 amino acids) assessed as inhibition of proteolytic cleavage of Rhodamine-EVNLDAEFK-Quencher substrate after 35 mins by FRET assay
- ChEMBL_973993 (CHEMBL2410318) Inhibition of N-terminal GST-tagged human PLK4 (1 to 391 amino acids) expressed in Escherichia coli using TMB as substrate after 30 mins by indirect ELISA assay
- Competitive Ligand Binding Assay Utilizing an analytical ultracentrifuge, the binding constants of various amino acids and isoleucine analogues to IleRS were estimated from their competition with radioactively labeled L-isoleucine.
- ChEMBL_1448250 (CHEMBL3375023) Inhibition of histidine-tagged recombinant EGFR cytoplasmic domain (amino acids 645-1186) (unknown origin) expressed in Sf9 cells assessed as reduction in enzyme autophosphorylation by DELFIA/time-resolved fluorometry
- ChEMBL_1520320 (CHEMBL3626370) Displacement of [3H]-DHT from human GST fused AR-LBD (627 to 919 amino acids) transfected in Escherichia coli HB 101 after 15 hrs by liquid scintillation counting assay
- ChEMBL_1719680 (CHEMBL4134680) Inhibition of recombinant LSD1 (157 to 852 amino acids) (unknown origin) expressed in Escherichia coli BL21(DE) using H3K4me2 substrate by amplex red and horseradish peroxidase based fluorescence assay
- ChEMBL_1759896 (CHEMBL4194904) Binding affinity to BRD2 bromodomain 1 to 2 (G73 to A560 amino acids) (unknown origin) using Alexa647-labeled BET-inhibitor as fluorescent probe by bromodomain TR-FRET binding assay
- ChEMBL_1759897 (CHEMBL4194905) Binding affinity to BRD3 bromodomain 1 to 2 (P24 to P416 amino acids) (unknown origin) using Alexa647-labeled BET-inhibitor as fluorescent probe by bromodomain TR-FRET binding assay
- ChEMBL_2132786 (CHEMBL4842301) Inhibition of ACSS2 in human HCT-15 cells assessed as inhibition of 14C acetate incorporation into fatty acids measured after 24 hrs by scintillation counting based cellular lipids assay
- ChEMBL_967971 (CHEMBL2401075) Binding affinity to recombinant human His-tagged MDM2 (1 to 118 amino acids) using p53-based PMDM6-F as probe after 15 to 30 mins by fluorescence polarization assay
- ChEMBL_1290541 (CHEMBL3119990) Displacement of [3H]-raclopride from high-affinity state of human dopamine D2L receptor (443 amino acids) expressed in LTK deficient mouse fibroblasts after 60 mins by liquid scintillation counting analysis
- ChEMBL_1438398 (CHEMBL3383627) Inhibition of catalytically active human SIRT3 (102 to 399 amino acids) expressed in Escherichia coli BL21 (DE3) cells using fluorogenic 7-amino-4-methylcoumarin (AMC)-labeled peptide by fluorescence assay
- ChEMBL_1826717 (CHEMBL4326591) Inhibition of N-terminal His-tagged recombinant human AXL (473 to end amino acids) expressed by baculovirus in Sf9 cells using axltide substrate and ATP by ADP-Glo luminescence assay
- ChEMBL_1926625 (CHEMBL4429697) Inhibition of recombinant human C-terminal 6His-tagged JAK2 (808 to end amino acids) expressed in Sf21 cells measured after 1 hr in presence of ATP by TR-FRET assay
- ChEMBL_2253497 (CHEMBL5167707) Agonist activity at human CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay
- ChEMBL_2263838 Agonist activity at human recombinant CLpP (57 to 277 amino acids) expressed in Escherichia coli using fluorogenic peptide AC-WLA-AMC as substrate incubated for 10 mins by fluorescence based assay
- ChEMBL_1438404 (CHEMBL3383633) Inhibition of catalytically active human SIRT3 (102 to 399 amino acids) expressed in Escherichia coli BL21 (DE3) cells using (Ac)RHKK(Ac)-AMC substrate by fluorescence assay based enzyme kinetic analysis
- ChEMBL_1457123 (CHEMBL3369467) Inhibition of c-terminal 6xHis-tagged Bcl-2 (amino acids 1 to 204) (unknown origin) preincubated for 1 hr prior to substrate addition measured after 20 mins by fluorescence polarization assay
- ChEMBL_1457124 (CHEMBL3369468) Inhibition of c-terminal 6xHis-tagged Bcl-xL (amino acids 1 to 209) (unknown origin) preincubated for 1 hr prior to substrate addition measured after 20 mins by fluorescence polarization assay
- ChEMBL_1619576 (CHEMBL3861745) Inhibition of N-terminal GST tagged human TrkA cytoplasmic domain (436 to 790 amino acids) pre-incubated for 15 mins before peptide substrate addition for 180 mins by fluorescence based assay
- ChEMBL_1619577 (CHEMBL3861746) Inhibition of N-terminal GST tagged human TrkB cytoplasmic domain (456 to 822 amino acids) pre-incubated for 15 mins before peptide substrate addition for 180 mins by fluorescence based assay
- ChEMBL_1759876 (CHEMBL4194884) Binding affinity to His-tagged BRD4 bromodomain 1 to 2 (K57 to K550 amino acids) (unknown origin) using Alexa647-labeled BET-inhibitor as fluorescent probe by bromodomain TR-FRET binding assay
- ChEMBL_1799155 (CHEMBL4271447) Inhibition of human recombinant CDK9/cyclin T expressed in insect cells using pRb fragment (773 to 928 amino acids) and [gamma-33P]ATP incubated fro 30 mins by scintillation counting analysis
- ChEMBL_965921 (CHEMBL2394352) Inhibition of human recombinant CLK1 (148 to 484 amino acids) expressed in Escherichia coli BL21(DE3) using AFRREWSPGKEAKK as substrate preincubated for 10 mins prior to substrate addition by LDH assay
- ChEMBL_966838 (CHEMBL2400839) Displacement of [3H]SP1-7 from substance P receptor (1 to 7 amino acids) binding site in Sprague-Dawley rat spinal cord membranes after 60 mins by liquid scintillation counting analysis
- ChEMBL_1453678 (CHEMBL3363784) Binding affinity to human recombinant N-terminal Avi-tagged glutamate carboxypeptidase 2 extracellular domain (44 to 750 amino acids) using biotin-tagged compound immobilized on neutravidin after 9 mins by SPR assay
- ChEMBL_1523511 (CHEMBL3631015) Inhibition of N-terminally GST- tagged human DLK catalytic domain (1 to 520 amino acids) using N-terminally HIS-tagged MKK4 K131M as substrate incubated for 60 mins by TR-FRET assay
- ChEMBL_1905311 (CHEMBL4407669) Inhibition of GST-tagged recombinant human DDR1 (440 to 876 amino acids) expressed in baculovirus using fluorescein-poly GAT as substrate after 1 hr by FRET-based LanthaScreen Eu kinase binding assay
- ChEBML_1691957 Inhibition of protease activity of recombinant Clostridium botulinum BoNT/A light chain (425 amino acids) using SNAP-25 as substrate preincubated for 20 followed by substrate addition measured for 25 mins by FRET analysis
- ChEMBL_1434484 (CHEMBL3388870) Inhibition of human recombinant KDM1A/CoREST expressed in Escherichia coli assessed as reduction in H2O2 release using synthetic mono-methylated H3-K4 peptide (21 amino acids) substrate by horseradish peroxidase coupled enzyme assay
- ChEMBL_863264 (CHEMBL2176207) Inhibition of human recombinant SIRT2 expressed in Escherichia coli cells using acetylated Lys side chain amino acids 379-382 (Arg-His-Lys-Lys(Ac)) p53 conjugated with aminomethylcoumarin as substrate by fluorescence assay
- ChEMBL_863265 (CHEMBL2176208) Inhibition of human recombinant SIRT1 expressed in Escherichia coli cells using acetylated Lys side chain amino acids 379-382 (Arg-His-Lys-Lys(Ac)) p53 conjugated with aminomethylcoumarin as substrate by fluorescence assay
- ChEMBL_1438405 (CHEMBL3383634) Inhibition of catalytically active human SIRT3 (102 to 399 amino acids) expressed in Escherichia coli BL21 (DE3) cells using (Ac)RHKK(Ac)-AMC substrate by fluorescence assay based Morrison's equation based enzyme kinetic analysis
- ChEMBL_1691957 (CHEMBL4042606) Inhibition of protease activity of recombinant Clostridium botulinum BoNT/A light chain (425 amino acids) using SNAP-25 as substrate preincubated for 20 followed by substrate addition measured for 25 mins by FRET analysis
- ChEMBL_1691958 (CHEMBL4042607) Uncompetitive inhibition of recombinant Clostridium botulinum BoNT/A light chain (425 amino acids) using SNAP-25 as substrate preincubated for 20 followed by substrate addition measured for 25 mins by Lineweaver-Burk plot analysis
- ChEMBL_1798921 (CHEMBL4271213) Inhibition of 6x-His-tagged human EGFR cytoplasmic domain (645 to 1186 amino acids) assessed as reduction in autophosphorylation pre-incubated for 10 mins and measured after 1 hr by DELFIA/time-resolved fluorometry
- ChEMBL_772464 (CHEMBL1839255) Agonist activity at human amino-terminal polyhistidine-tagged FXR alpha LBD (amino acids 237 to 472) assessed as cofactor peptide SRC-1 interaction with receptor ligand binding domain after 2 hrs by FRET assay
- ChEMBL_1335833 (CHEMBL3239942) Inhibition of human coronavirus NL63 PLP2 (amino acids 1565 to 1894) expressed in Escherichia coli BL21 (DE3) cells assessed as reduction of AMC release using Z-RLRGG-AMC as substrate by multimode plate reader analysis
- ChEMBL_1476207 (CHEMBL3429393) Inhibition of PTP1B catalytic domain (1 to 321 amino acids) (unknown origin) expressed in Escherichia coli Rosetta (DE3) incubated for 30 mins followed by UV irradiation with 365 nm for 45 mins by pNPP assay
- ChEMBL_1798716 (CHEMBL4271008) Inhibition of wild type N-terminal GST tagged human recombinant EGFR (695 to end amino acids) expressed in baculovirus infected Sf9 insect cells using Poly (4:1 Glu, Tyr) Peptide substrate by ADP-Glo assay
- ChEMBL_1860111 (CHEMBL4360967) Displacement of Alexafluor labelled kinase tracer314 from recombinant human C-terminal GST-tagged mTOR (1360 to 2549 amino acids) expressed in insect cells incubated for 1 hr by FRET-based LanthaScreen Eu kinase binding assay
- ChEMBL_816345 (CHEMBL2024743) Inhibition of N-terminal hexa-histidine tagged human cloned Eg5 (1 to 368 amino acids) expressed in Escherichia coli BL21 (DE3) assessed as reduction in basal ATPase activity by pyruvate kinase/lactate dehydrogenase-linked assay
- ChEMBL_1438406 (CHEMBL3383635) Competitive inhibition of catalytically active human SIRT3 (102 to 399 amino acids) expressed in Escherichia coli BL21 (DE3) cells using varying (Ac)RHKK(Ac)-AMC substrate by fluorescence assay based Morrison's equation based enzyme kinetic analysis
- ChEMBL_1465147 (CHEMBL3405660) Inhibition of human recombinant SIRT5 isoform 1 (34 to 302 amino acids) expressed in Escherichia coli BL21 (DE3) codon plus RIL cells assessed as reduction in deacetylase activity using acetylated chicken histone substrate and [3H]-NAD+
- ChEMBL_1476206 (CHEMBL3429392) Inhibition of PTP1B catalytic domain (1 to 321 amino acids) (unknown origin) expressed in Escherichia coli Rosetta (DE3) incubated for 30 mins in absence of UV irradiation with 365 nm for 45 mins by pNPP assay
- ChEMBL_1476965 (CHEMBL3430220) Inhibition of GST-tagged human recombinant EGFR catalytic domain (668 to 1210 amino acids) L858R mutant expressed in Sf9 cells pre-incubated for 30 mins before ATP and substrate addition by homogeneous time-resolved FRET assay
- ChEMBL_1798715 (CHEMBL4271007) Inhibition of N-terminal GST tagged human recombinant EGFR L858R/T790M mutant (695 to end amino acids) expressed in baculovirus infected Sf9 insect cells using Poly (4:1 Glu, Tyr) Peptide substrate by ADP-Glo assay
- ChEMBL_1806397 (CHEMBL4305756) Displacement of tracer 222 from GST-tagged recombinant human AAK1 catalytic domain (1 to 510 amino acids) expressed in insect cells shaken for 30 secs and incubated for 1 hr by LanthaScreen Eu kinase binding assay
- ChEMBL_1970699 (CHEMBL4603517) Inhibition of recombinant human GST-tagged LRRK2 catalytic domain (970 to 2527 amino acids) expressed in baculovirus expression system using ERM (LRRKtide) peptide as substrate incubated for 60 mins in presence of ATP by Adapta assay
- ChEMBL_816346 (CHEMBL2024744) Inhibition of N-terminal hexa-histidine tagged human cloned Eg5 (1 to 368 amino acids) expressed in Escherichia coli BL21 (DE3) assessed as reduction of MT-stimulated ATPase activity by pyruvate kinase/lactate dehydrogenase-linked assay
- ChEMBL_1476966 (CHEMBL3430221) Inhibition of GST-tagged human recombinant EGFR catalytic domain (668 to 1210 amino acids) T790M/L858R mutant expressed in Sf9 cells pre-incubated for 30 mins before ATP and substrate addition by homogeneous time-resolved FRET assay
- ChEMBL_1499748 (CHEMBL3585197) Inhibition of ROCK1 (6 to 553 amino acids) (unknown origin) using Lys-Lys-Arg-Asn-Arg-Thr-Leu-Ser-Val as substrate preincubated for 15 mins followed by ATP addition by pyruvate kinase/lactate dehydrogenase coupled assay
- ChEMBL_1579231 (CHEMBL3812311) Inhibition of N-terminal GST-tagged recombinant human PDGFRbeta (amino acids 557-end) expressed in baculovirus infected insect Sf9 cells using Poly(4:1 Glu, Tyr) peptide as substrate after 1 hr by promega ADP-glo assay
- ChEMBL_1806441 (CHEMBL4305800) Inhibition of C-terminal recombinant human ClpP (57 to 277 amino acids) expressed in Escherichia coli Rosetta2 cells using Suc-Leu-Tyr-AMC as substrate incubated for 1 hr and measured for 90 mins by fluorescence assay
- ChEMBL_1873666 (CHEMBL4374955) Inhibition of bacterial N-terminal His-tagged TEV protease site linked TEM-1 (24 to 286 amino acids) expressed in Escherichia coli Transetta (DE3) preincubated for 10 mins followed by FC5 fluorescent substrate addition by fluorescence assay
- ChEMBL_1873903 (CHEMBL4375192) Covalent inhibition of N-terminal GST-fused human BTK (2-659(end) amino acids) expressed in baculovirus expression system using FITC-AHA-EEPLYWSFPAKKK-NH2 as substrate incubated for 90 mins by microfluidic off-Chip Mobility Shift Assay
- ChEMBL_1874103 (CHEMBL4375392) Inhibition of integrin alphavbeta1 (unknown origin) expressed in human A549 cells assessed as reduction in cell adhesion to GST-LAP1 (242 to 252 amino acids) incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
- ChEMBL_1874104 (CHEMBL4375393) Inhibition of integrin alphavbeta3 (unknown origin) expressed in human K562 cells assessed as reduction in cell adhesion to GST-LAP1 (242 to 252 amino acids) incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
- ChEMBL_1874106 (CHEMBL4375395) Inhibition of integrin alphavbeta8 (unknown origin) expressed in human K562 cells assessed as reduction in cell adhesion to GST-LAP1 (242 to 252 amino acids) incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
- ChEMBL_1874107 (CHEMBL4375396) Inhibition of integrin alphavbeta6 (unknown origin) expressed in human K562 cells assessed as reduction in cell adhesion to GST-LAP1 (242 to 252 amino acids) incubated for 30 mins by fluorescent probe BCECF-AM based fluorescence assay
- ChEMBL_1467488 (CHEMBL3411111) Inhibition of human recombinant KDM1A/CoREST complex expressed in Escherichia coli using mono-methylated H3-K4 peptide containing 21 amino acids as substrate preincubated for 15 mins followed by substrate addition measured for 12 mins by fluorescence assay
- ChEMBL_1472393 (CHEMBL3420114) Inhibition of hexahistidine-tagged human recombinant ARTD8 catalytic domain (1611 to 1801 amino acids) expressed in Escherichia coli BL21(DE3) assessed as inhibition of ADP-ribosyltransferase activity incubated for 15 mins using biotin-NAD+ by chemiluminescence detection based assay
- ChEMBL_1472394 (CHEMBL3420115) Inhibition of hexahistidine-tagged human recombinant ARTD7 catalytic domain (459 to 656 amino acids) expressed in Escherichia coli BL21(DE3) assessed as inhibition of ADP-ribosyltransferase activity incubated for 15 mins using biotin-NAD+ by chemiluminescence detection based assay
- ChEMBL_1496877 (CHEMBL3580357) Inhibition of hexa-histidine tagged recombinant tankyrase 1 biotinylated catalytic domain (amino acids 1106 to 1325) (unknown origin) expressed in Escherichia coli BL21 (DE3) assessed as reduction in ADP-ribosyl transferase activity using NAD+ by chemiluminescence detection based assay
- ChEMBL_2050770 (CHEMBL4705469) Inhibition of N-terminal GST tagged wild-type human ALK cytoplasmic domain (1058-1620 amino acids) expressed Sf9 cells pre-incubated for 30 mins before addition of Ulight-CKKSRGDYMTMQIG substrate and measured after 90 mins by fluorescence based assay
- ChEMBL_785410 (CHEMBL1919789) Inhibition of C-terminal His6-tagged human DNA polymerase eta (amino acids 1 to 511) using poly(dA)/oligo(dT)18 (A/T = 2/1) and dTTP as the DNA template-primer and nucleotide substrate after 60 mins
- ChEMBL_785412 (CHEMBL1919791) Inhibition of C-terminal His6-tagged human DNA polymerase kappa (amino acids 1 to 560) using poly(dA)/oligo(dT)18 (A/T = 2/1) and dTTP as the DNA template-primer and nucleotide substrate after 60 mins
- ChEMBL_787970 (CHEMBL1918904) Inhibition of full length human MMP2 (amino acids 1 to 660) using acetyl-Cys(Eu)-Pro-Leu-Gly-Leu-Lys-(QSY7)-Ala-Arg-amide as substrate preincubated for 1 hrs before substrate addition measured after 15 mins by fluorimetry
- ChEMBL_787971 (CHEMBL1918905) Inhibition of human MMP9 catalytic domain (amino acids 107 to 446) using acetyl-Cys(Eu)-Pro-Leu-Gly-Leu-Lys-(QSY7)-Ala-Arg-amide as substrate preincubated for 1 hrs before substrate addition measured after 15 mins by fluorimetry
- ChEMBL_787972 (CHEMBL1918906) Inhibition of human MMP1 catalytic domain (amino acids 100 to 262) using acetyl-Cys(Eu)-Pro-Leu-Gly-Leu-Lys-(QSY7)-Ala-Arg-amide as substrate preincubated for 1 hrs before substrate addition measured after 15 mins by fluorimetry
- ChEMBL_787973 (CHEMBL1918907) Inhibition of human MMP3 catalytic domain (amino acids 100 to 265) using acetyl-Cys(Eu)-Pro-Leu-Gly-Leu-Lys-(QSY7)-Ala-Arg-amide as substrate preincubated for 1 hrs before substrate addition measured after 15 mins by fluorimetry
- ChEMBL_787974 (CHEMBL1918908) Inhibition of human MMP13 catalytic domain (amino acids 103 to 268) using acetyl-Cys(Eu)-Pro-Leu-Gly-Leu-Lys-(QSY7)-Ala-Arg-amide as substrate preincubated for 1 hrs before substrate addition measured after 15 mins by fluorimetry
- ChEMBL_1438407 (CHEMBL3383636) Non-competitive inhibition of catalytically active human SIRT3 (102 to 399 amino acids) expressed in Escherichia coli BL21 (DE3) cells using (Ac)RHKK(Ac)-AMC substrate and varying NAD+ levels by fluorescence assay based Morrison's equation based enzyme kinetic analysis
- ChEMBL_1476209 (CHEMBL3429395) Inhibition of PTP1B catalytic domain (1 to 321 amino acids) (unknown origin) expressed in Escherichia coli Rosetta (DE3) incubated for 30 mins followed by UV irradiation with 365 nm for 45 mins in presence of 1 mM DTT by pNPP assay
- ChEMBL_938233 (CHEMBL2328536) Inhibition of C-terminal His-tagged human recombinant HDAC9 (amino acids 604- 1066) expressed in baculovirus expression system using fluorogenic acetylated peptide as substrate preincubated with enzyme for 10 mins prior to substrate addition measured after 60 mins by fluorescence analysis
- ChEMBL_966729 (CHEMBL2400289) Inhibition of GST-tagged Aurora kinase A catalytic domain (123 to 401 amino acids) (unknown origin) expressed in sf9 cells using tetra(LRRWSLG) as substrate preincubated for 15 mins prior to substrate addition measured after 90 mins by luminescence assay
- Ligand-Induced Uptake of [35S]-GTP-gamma-S EC50s were determined by measuring the binding of [35S]-GTP-gamma-S to S1P receptors expressed in transfected Chinese hamster ovary (CHO) cell membranes. It is found that these modified 3-arylpropionic acids appeared to be more potent when evaluated in the functional assay than in the competitive binding assay, and their EC50 values served as a better guide for interpreting in vivo activity. All 3-arylpropionic acids and their modified analogs are found to be inactive against S1P2,4 receptors (IC50 > 10 uM).
- ChEMBL_1363643 (CHEMBL3293161) Inhibition of wild type human recombinant ALK kinase domain (amino acids 1093 to 1141) expressed in baculovirus system using 5'FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to ATP addition measured after 1 hr by microfluidic mobility shift assay
- ChEMBL_1363644 (CHEMBL3293162) Inhibition of human recombinant ALK L1196M mutant kinase domain (amino acids 1093 to 1141) expressed in baculovirus system using 5'FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to ATP addition measured after 1 hr by microfluidic mobility shift assay
- ChEMBL_1476208 (CHEMBL3429394) Inhibition of PTP1B catalytic domain (1 to 321 amino acids) (unknown origin) expressed in Escherichia coli Rosetta (DE3) incubated for 30 mins in absence of UV irradiation with 365 nm for 45 mins and in presence of 1 mM DTT by pNPP assay
- ChEMBL_1843891 (CHEMBL4344318) Inhibition of N-terminal His6-tagged human Bcl-xL (with internal deletion of 45 to 85 amino acids and C-terminal truncation for 212 to 233 residues) expressed in Escherichia coli Rosetta2 DE3 by fluorescent labeled FAM-Bid peptide based fluorescence polarization assay
- ChEMBL_1873760 (CHEMBL4375049) Inhibition of human C-terminal His-tagged and N-terminal GST-tagged EGFR L858R/T790M/C797S triple mutant ( 668 to 1210 amino acids) expressed in baculovirus infected Sf9 insect cells using Poly(Glu,Tyr) 4:1 as substrate after 60 mins by ELISA
- ChEMBL_1995343 (CHEMBL4629238) Inhibition of N-terminal GST-tagged human FGFR3 cytoplasmic domain (436-806 end amino acids residues) expressed in baculovirus expression system preincubated for 30 to 120 mins followed by incubation with substrate and ATP for 30 mins by off-chip mobility shift assay
- ChEMBL_1995346 (CHEMBL4629241) Inhibition of N-terminal GST-tagged human FGFR1 cytoplasmic domain (398-822 end amino acids residues) expressed in baculovirus expression system preincubated for 30 to 120 mins followed by incubation with substrate and ATP for 30 mins by off-chip mobility shift assay
- ChEMBL_1995347 (CHEMBL4629242) Inhibition of N-terminal GST-tagged human FGFR2 cytoplasmic domain (399-821 end amino acids residues) expressed in baculovirus expression system preincubated for 30 to 120 mins followed by incubation with substrate and ATP for 30 mins by off-chip mobility shift assay
- ChEMBL_1995348 (CHEMBL4629243) Inhibition of N-terminal GST-tagged human FGFR4 cytoplasmic domain (460-802 end amino acids residues) expressed in baculovirus expression system preincubated for 30 to 120 mins followed by incubation with substrate and ATP for 30 mins by off-chip mobility shift assay
- ChEMBL_2105715 (CHEMBL4814390) Inhibition of N-terminal hexahistidine-tagged human LSD1 (1 to 852 amino acids) expressed in Escherichia coli BL21 (DE3) cells using H3K4me2 peptide as substrate preincubated for 5 mins followed by substrate addition and measured for 30 mins by peroxidase-coupled method
- Enzyme Assay ATR for use in the in vitro enzyme assay was obtained from HeLa nuclear extract (CIL Biotech, Mons, Belgium) by immunoprecipitation with rabbit polycolonal antiserum raised to amino acids 400-480 of ATR (Tibbetts R S et, al, 1999, GenesDev.13:152-157).
- ChEMBL_1576591 (CHEMBL3807386) Inhibition of wild type His-tagged c-KIT (544 to 976 amino acids) (unknown origin) expressed in insect cells using poly[Glu:Tyr] (4:1) as substrate preincubated for 20 mins followed by [33P-gamma]ATP addition and subsequent inhibition for 2 hrs by radiometric assay
- ChEMBL_1576592 (CHEMBL3807387) Inhibition of N-terminal GST-His-tagged c-KIT (544 to 976 amino acids) D816V mutant (unknown origin) expressed in Sf9 insect cells using poly[Glu:Tyr] (4:1) as substrate preincubated for 20 mins followed by [33P-gamma]ATP addition and subsequent inhibition for 2 hrs by radiometric assay
- LRRK2 Enzymatic Assay LRRKtide substrate (peptide sequence RLGRDKYKTLRQIRQ, derived from human ezrin [amino acids 561-573], moesin [amino acids 539-553] and radixin [amino acids 558-570], obtained from SignalChem, catalogue #L10-58, reconstituted in 20 mM Tris-HCl at pH 7.5 to a final concentration of 1 mg/mL, assay concentration 20 μM) and recombinant human LRRK2 (catalytic domain only [amino acids 970-2527], GST-tagged, expressed in insect cells, obtained from ThermoFisher Scientific, catalogue #PV4874, 0.35 mg/mL, assay concentration 30 nM) were mixed in assay buffer (20 mM Hepes pH 7.5, 10 mM MgCl, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM NaVO, 2 mM DTT, 1% DMSO). Compounds of interest (in DMSO, serial 3-fold dilution from 10 μM to 0.5 nM) or control (1% DMSO) were dispensed into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range). After incubation at room temperature for 20 minutes, the kinase reaction was initiated by addition of [P]-ATP (Specific activity 10 μCi/μl) and the mixture was incubated at room temperature for 2 hours. The reaction was then stopped by spotting the reaction mixture on strips of phosphocellulose P81 paper. Following washing, the radioactivity of the P81 paper was measured and kinase activity data were expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions.
- TR-FRET Assay Ten nanomolar of 6× Histidine-tagged BIR2 domain, corresponding to amino acids 124-240 of XIAP, or BIR3 domain, corresponding to amino acids 241-356 of XIAP, was mixed with 20 nM of the peptide AVPIAQKSEK-(ε-biotin)-OH 1:2 TFA, in the presence of 50 mM Tris-Cl, pH 7.5, 100 mM NaCl, 1 mM dithiothreitol (DTT) and 0.1 mg/mL bovine serum albumin (BSA). Following a 45 min. incubation at 37° C., Europium-Streptavidin and Allophycocyanin conjugated anti-Histidine antibody were added to a final concentration of 1.5 nM and 15 nM, respectively. Time-resolved fluorescence resonance energy transfer (TR-FRET) signals were measured 1 hour later at room temperature.
- FAS Inhibitory Assay To each microtube (final volume: 100 μL), FAS was added (20-30 μg protein) in a buffer containing 100 mM potassium phosphate (pH 7.0), 2.5 mM dithiothreitol and 2.0 mM EDTA with or without test compounds. The mixtures were preincubated at 37°C for 60 min and the reaction was started by the addition of a substrate mixture containing 0.25 mM NADPH, 0.4 nmol of malonyl CoA and 0.02 μCi of [3H] acetyl CoA. Following incubation at 37°C for 10 min, the reaction was terminated with 60% HClO4. Fatty acids were extracted with 1 mL of hexane and incorporation of radioactivity into the fatty acids was assessed by scintillation counting [Na et al., Bioorg. Med. Chem. Lett., 16:4738-4742].
- Pseudotyped HCV particle (HCVpp) reporter assay Plasmids expressing HCV E1 and E2 envelope proteins of GT1a H77 strain (Proc Natl Acad Sci USA 1997 94:8738-43) or GT1b Con1 strain (Science 1999 285:110-3) were constructed by cloning the nucleic acids encoding the last 60 amino acids of HCV core protein and all of the HCV E1 and E2 proteins into pcDNA3.1(+) vector. Plasmid pVSV-G expressing the glycoprotein G of the vesicular stomatitis virus (VSV G) is from Clontech (cat #631530). The HIV packaging construct expressing the firefly luciferase reporter gene was modified based on the envelope defective pNL.4.3.Luc-R .E vector (Virology 1995 206:935-44) by further deleting part of the HIV envelope protein.
- TR-FRET Assay Ten nanomolar of 6x Histidine-tagged BIR2 domain, corresponding to amino acids 124-240 of XIAP, or BIR3 domain, corresponding to amino acids 241-356 of XIAP, was mixed with 20 nM of the peptide AVPIAQKSEK-(8-biotin)-OH 1:2 TFA, in the presence of 50 mM Tris-C1, pH 7.5, 100 mM NaCl, 1 mM dithiothreitol (DTT) and 0.1 mg/mL bovine serum albumin (BSA). Following a 45 min. incubation at 37° C., Europium-Streptavidin and Allophycocyanin conjugated anti-Histidine antibody were added to a final concentration of 1.5 nM and 15 nM, respectively. Time-resolved fluorescence resonance energy transfer (TR-FRET) signals were measured 1 hour later at room temperature. Test compound potency was assessed at 10 serially diluted concentrations.
- Release Assay SH-SY5Y cells were cultured in DMEM/F-12 with Glutamax, 10% FCS and 1% non-essential amino acids and cryopreserved and stored at -140 C. at a concentration of 7.5-9.5x106 cells per vial. Thaw cells and seed at a conc. of around 10000 cells/well in DMEM/F-12 with Glutamax, 10% FCS and 1% non-essential amino acids to a 384-well tissue culture treated plate, 100 uL cell susp/well. The cell plates were then incubated for 7-24 h at 37 C., 5% CO2. The cell medium was removed, followed by addition of 30 uL compound diluted in DMEM/F-12 with Glutamax, 10% FCS, 1% non-essential amino acids and 1% PeSt to a final conc. of 1% DMSO. The compounds were incubated with the cells for 17 h (overnight) at 37 C., 5% CO2. Meso Scale Discovery (MSD) plates were used for the detection of sAPPbeta release. MSD sAPPbeta plates were blocked in 1% BSA in Tris wash buffer (40 uL/well) for 1 h on shake at r.t. and washed 1 time in Tris wash buffer (40 uL/well).
- Release Assay SH-SY5Y cells were cultured in DMEM/F-12 with Glutamax, 10% FCS and 1% non-essential amino acids and cryopreserved and stored at -140 C. at a concentration of 7.5-9.5x106 cells per vial. Thaw cells and seed at a conc. of around 10000 cells/well in DMEM/F-12 with Glutamax, 10% FCS and 1% non-essential amino acids to a 384-well tissue culture treated plate, 1004, cell susp/well. The cell plates were then incubated for 7-24 h at 37 C., 5% CO2. The cell medium was removed, followed by addition of 30 uL compound diluted in DMEM/F-12 with Glutamax, 10% FCS, 1% non-essential amino acids and 1% PeSt to a final conc. of 1% DMSO. The compounds were incubated with the cells for 17 h (overnight) at 37 C., 5% CO2. Meso Scale Discovery (MSD) plates were used for the detection of sAPPbeta release. MSD sAPPbeta plates were blocked in 1% BSA in Tris wash buffer (40 uL/well) for 1 h on shake at r.t. and washed 1 time in Tris wash buffer (40 uL/well).
- SOS-Catalyzed Nucleotide Exchange Assay (version 1) Recombinant KRAS G12C (amino acids 1-169, SEQ ID NO:1), KRAS G12D (amino acids 1-169, SEQ ID NO:2), KRAS G12V (amino acids 1-169, SEQ ID NO:3) and SOS1 (amino acids 564-1049, SEQ ID NO:4) proteins were expressed in E. coli and purified by affinity chromatography. To prepare each BODIPY FL GDP-bound KRAS mutant protein, 50 uM KRAS mutant proteins were incubated with 0.5 mM BODIPY FL GDP (Invitrogen, G22360) in a loading buffer (20 mM Tris-HCl (pH 7.5), 50 mM NaCl, 1 mM DTT and 2.5 mM EDTA) for 1 hour on ice. After the incubation, MgCl2 was added to a final concentration of 10 mM, followed by incubation at room temperature for 30 minutes. The mixtures were allowed to pass through a NAP-5 column to remove free nucleotides and purified BODIPY FL GDP-bound KRAS G12C, G12D and G12V proteins were used for compound evaluation. For the measurement of the inhibitory activity of compounds on GDP-GTP exchange rate of recombinant KRAS mutants, each BODIPY FL GDP-bound KRAS mutant protein whose concentration is 25 nM was incubated with various concentrations of compound in a reaction buffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM MgCl2, 2 mM DTT, 0.1% Tween 20) at 25 C. for 1 hour. After the incubation, recombinant SOS1 and GMPPNP (Jena Bioscience GmbH, NU-401) were added and incubated at room temperature for 30 minutes to proceed SOS1-dependent GDP-GTP exchange reaction on KRAS mutants.
- SOS-Catalyzed Nucleotide Exchange Assay (version 2) Recombinant KRAS G12C (amino acids 1-169, SEQ ID NO:1), KRAS G12D (amino acids 1-169, SEQ ID NO:2), KRAS G12V (amino acids 1-169, SEQ ID NO:3) and SOS1 (amino acids 564-1049, SEQ ID NO:4) proteins were expressed in E. coli and purified by affinity chromatography. To prepare each BODIPY FL GDP-bound KRAS mutant protein, 50 uM KRAS mutant proteins were incubated with 0.5 mM BODIPY FL GDP (Invitrogen, G22360) in a loading buffer (20 mM Tris-HCl (pH 7.5), 50 mM NaCl, 1 mM DTT and 2.5 mM EDTA) for 1 hour on ice. After the incubation, MgCl2 was added to a final concentration of 10 mM, followed by incubation at room temperature for 30 minutes. The mixtures were allowed to pass through a NAP-5 column to remove free nucleotides and purified BODIPY FL GDP-bound KRAS G12C, G12D and G12V proteins were used for compound evaluation. For the measurement of the inhibitory activity of compounds on GDP-GTP exchange rate of recombinant KRAS mutants, each BODIPY FL GDP-bound KRAS mutant protein whose concentration is 2.5 nM was incubated with various concentrations of compound in a reaction buffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM MgCl2, 2 mM DTT, 0.1% Tween 20) at 25 C. for 1 hour. After the incubation, recombinant SOS1 and GMPPNP (Jena Bioscience GmbH, NU-401) were added and incubated at room temperature for 30 minutes to proceed SOS1-dependent GDP-GTP exchange reaction on KRAS mutants.
- ChEMBL_1570257 (CHEMBL3795199) Binding affinity to FKBP51 FK506-binding domain (1 to 140 amino acids) (unknown origin) incubated for 30 mins using fluorescein-conjugated 2-(5-((2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(3,3-dimethyl-2-oxopentanoyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetamido)methyl)-6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid by competitive fluorescence polarization assay
- TR-FRET Assay Ten nanomolar of 6× Histidine-tagged BIR2 domain, corresponding to amino acids 124-240 of XIAP, or BIR3 domain, corresponding to amino acids 241-356 of XIAP, was mixed with 20 nM of the peptide AVPIAQKSEK-(ε-biotin)-OH 1:2 TFA, in the presence of 50 mM Tris-Cl, pH 7.5, 100 mM NaCl, 1 mM dithiothreitol (DTT) and 0.1 mg/mL bovine serum albumin (BSA). Following a 45 min. incubation at 37° C., Europium-Streptavidin and Allophycocyanin conjugated anti-Histidine antibody were added to a final concentration of 1.5 nM and 15 nM, respectively. Time-resolved fluorescence resonance energy transfer (TR-FRET) signals were measured 1 hour later at room temperature. Test compound potency was assessed at 10 serially diluted concentrations.
- Binding Assay The murine STING [3H] 2′,3′-cGAMP scintillation proximity competition binding assay was performed in the same manner as the human STING competition binding assay (described above) with the exception that murine STING protein (amino acids 154-378, SEQ ID NO: 3) was utilized. 2′,2′-cGAMP was used as a reference compound and had an IC50 of 0.055 μM.
- Inhibition Assay Jak2: Compounds of Formula I were screened for their ability to inhibit Jak2 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 10 μM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 4 nM Jak2 in a total volume of 20 μL. Human Jak2 kinase domain comprising amino acids 808-1132.
- Enzyme Inhibition Assay Enzyme inhibition studies were performed using recombinant JAK1 (amino acids 866-1154, Life Technologies, #PV4774, Carlsbad, Calif.), JAK2 (amino acids 831-1132, AstraZeneca R&D Boston), or JAK3 (amino acids 781-1124, AstraZeneca R&D Boston) under buffer conditions of 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween-20, 50 μg/ml BSA, and 10 mM MgCl2. JAK enzyme was expressed as N-terminal GST fusion in insect cells and purified by glutathione-affinity and size-exclusion chromatographies. Enzymes were assayed at their approximated high end of physiological ATP concentration of 5 mM, in the presence of inhibitor dosed at 30, 3, 0.3, 0.03, 0.003 and 0 μM final test concentrations.For JAK1, 4 nM of enzyme was incubated with 1.5 μM peptide substrate (FITC-C6-KKHTDDGYMPMSPGVA-NH2 (SEQ ID NO:1), Intonation, Boston, Mass.). For JAK2, 0.3 nM enzyme was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO:2), Intonation, Boston, Mass.), For JAK3, 0.1 nM enzyme was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NII2 (SEQ ID NO:2), Intonation, Boston, Mass.). Phosphorylated and unphosphotylated peptides were separated and quantified by a Caliper LC3000 system (Caliper Life Sciences, MA) for calculating percent inhibition.
- Time Resolved Fluorescence Energy Transfer (TR-FRET) Assay The inhibition of p53-MDM2 and p53-MDM4 interactions is measured by time resolved fluorescence energy transfer (TR-FRET). Fluorescence energy transfer (or Foerster resonance energy transfer) describes an energy transfer between donor and acceptor fluorescent molecules. For this assay, human MDM2 protein (amino acids 2-188) and human MDM4 protein (amino acids 2-185), tagged with a C-terminal biotin moiety, are used in combination with a Europium labeled streptavidin (Perkin Elmer, Inc., Waltham, MA, USA) serving as the donor fluorophore. The p53 derived, Cy5 labeled peptide Cy5-TFSDLWKLL (p53 aa18-26) is the energy acceptor. Upon excitation of the donor molecule at 340nm, binding interaction between MDM2 or MDM4 and the p53 peptide induces energy transfer and enhanced response at the acceptor emission wavelength at 665 nm.
- Time Resolved Fluorescence Energy Transfer (TR-FRET) Assay The inhibition of p53-MDM2 and p53-MDM4 interactions is measured by time resolved fluorescence energy transfer (TR-FRET). Fluorescence energy transfer (or Foerster resonance energy transfer) describes an energy transfer between donor and acceptor fluorescent molecules. For this assay, human MDM2 protein (amino acids 2-188) and human MDM4 protein (amino acids 2-185), tagged with a C-terminal biotin moiety, are used in combination with a Europium labeled streptavidin (Perkin Elmer, Inc., Waltham, Mass., USA) serving as the donor fluorophore. The p53 derived, Cy5 labeled peptide Cy5-TFSDLWKLL (p53 aa18-26) is the energy acceptor. Upon excitation of the donor molecule at 340 nm, binding interaction between MDM2 or MDM4 and the p53 peptide induces energy transfer and enhanced response at the acceptor emission wavelength at 665 nm.
- Inhibition Assay Jak1: Compounds of Formula I were screened for their ability to inhibit Jak1 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 8 μM Omnia Y12 peptide (Catalog # IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 5 nM Jak1 in a total volume of 20 μL. GST-tagged human Jak1 kinase domain comprising amino acids 866-1154.
- Inhibition Assay Jak3: Compounds of Formula I were screened for their ability to inhibit Jak3 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 10 μM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 1.5 nM Jak3 in a total volume of 20 μL. GST-tagged human Jak3 kinase domain comprising amino acids 781-1124
- SOS1 GDP TR-FRET Assay This assay was used to identify compounds which competitively interact with the binding of KRAS protein to SOS1 in the presence of GDP. GST-tagged WT KRAS (amino acids 1-188), GST-tagged KRAS (amino acids 1-188) G12D and His- tagged SOS1 protein (amino acids 564-1049) was expressed in E. coli and purified. All protein and reaction solutions were prepared in assay buffer containing DPBS pH7.5, 0.1% BSA, and 0.05% Tween 20. Purified GST-tagged WT KRAS or KRAS G12D protein (37.5 nM final assay concentration) and GDP (Sigma, 10 μM final assay concentration) mixture, a serially diluted compound (top final concentration is 50 uM or 10 uM, 3-fold serially diluted, 10 points) and His-tagged SOS1 protein (18 nM final assay concentration) were added into the assay plates (384 well microplate, black, Corning) sequentially. Plates are incubated at 24° C. for 1 hr. Following the incubation, Mab Anti-6His-Tb cryptate (Cisbio) and Mab Anti GST-D2 (Cisbio) were added and further incubated at 24° C. for another 1 hr. The TR-FRET signals (ex337nm, em665nm/620nm) were read on BMG PHERAstar FSX instrument. The inhibition percentage of KRAS protein binding with SOS1 in presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm.
- TR-FRET Assay for BIR2 and BIR3 Ten nanomolar of 6× Histidine-tagged BIR2 domain, corresponding to amino acids 124-240 of XIAP, or BIR3 domain, corresponding to amino acids 241-356 of XIAP, was mixed with 20 nM of the peptide AVPIAQKSEK-(c-biotin)-OH 1:2 TFA, in the presence of 50 mM Tris-Cl, pH 7.5, 100 mM NaCl, 1 mM dithiothreitol (DTT) and 0.1 mg/mL bovine serum albumin (BSA). Following a 45 min. incubation at 37° C., Europium-Streptavidin and Allophycocyanin conjugated anti-Histidine antibody were added to a final concentration of 1.5 nM and 15 nM, respectively. Time-resolved fluorescence resonance energy transfer (TR-FRET) signals were measured 1 hour later at room temperature. Test compound potency was assessed at 10 serially diluted concentrations. Percentage of inhibition at each concentration was determined to generate an IC50 value for each test compound.
- Tet-Inducible cAMP Assay A human-mouse chimeric GPR119 expression construct encoding 3 copies of the FLAG epitope tag, the first 198 amino acids of human GPR119 and the C-terminal 137 amino acids of the mouse receptor was cloned into a tetracycline inducible vector pcDNA5/FRT/TO (Invitrogen #V6520-20), which includes a hygromycin-resistance marker. Tightly controlled receptor expression was achieved by stable integration of this construct into the genome of a specific host cell line, Flp-In-T-Rex-HEK293, expressing the tetracycline repressor (Invitrogen). Once a stable hygromycin-resistant cell line was generated, the cells were maintained at 37° C. in a humidified 5% CO2 atmosphere in culture medium consisting of Dulbecco's modified Eagle's medium (DMEM; Invitrogen #11960) supplemented with 2 mM L-glutamine, 10% fetal bovine serum, 200 μg/ml hygromycin B, and 15 μg/ml blasticidin.
- Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak2 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 10 μM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 4 nM Jak2 in a total volume of 20 μL. Human Jak2 kinase domain comprising amino acids 808-1132 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV4210).
- Jak1 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak1 using the general enzyme inhibition assay method, in which the assay mixture contained 500 uM ATP, 8 uM Omnia Y12 peptide (Catalog # IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 5 nM Jak1 in a total volume of 20 uL. GST-tagged human Jak1 kinase domain comprising amino acids 866-1154 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV4774).
- Jak2 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak2 using the general enzyme inhibition assay method, in which the assay mixture contained 500 uM ATP, 10 uM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 4 nM Jak2 in a total volume of 20 uL. Human Jak2 kinase domain comprising amino acids 808-1132 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV4210).
- Jak3 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak3 using the general enzyme inhibition assay method, in which the assay mixture contained 500 M ATP, 10 uM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 1.5 nM Jak3 in a total volume of 20 uL. GST-tagged human Jak3 kinase domain comprising amino acids 781-1124 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV3855).
- Fluorescence Resonance Energy Transfer (FRET) Assay Potency of test compounds were determined by measurement of their inhibition of BACE1 activity toward a fluorescent substrate. Experiments were performed by reference to the procedure as described in Ermolieff, et al. (Biochemistry 39:12450-12456 (2000), the teachings of which are incorporated hereby in their entirety). Briefly, the recombinant protease unit of BACE1 was prepared from E. coli expression as inclusion bodies, refolded, and purified as described in Lin, et al., (Proc. Nat. Acad. Sci. 97:1456-1460 (2000)). Fluorogenic substrate, MCA-SEVNLDAEFK(DNP)-NH2 (SEQ ID NO:1) was purchased. (M-2485, Bachem Americas, Torrance, Calif.). The substrate was derived from 10 amino acids of the human amyloid precursor protein (APP), with the Swedish variant amino acids at the beta-secretase cleavage site. The terminal amino acid was modified from arginine to lysine to facilitate derivatization with a functional group for detection by autofluorescence.
- Kat6a Activity Assay Recombinant human His-tagged Kat6a protein (amino acids 194-810), was purified in-house from Baculovirus-infected insect cells (Sf9). Histone H4 peptide (amino acids 1-24, SGRGKGGKGLGKGGAKRHRK-VLRD-K(Btn)-amide), which was used as substrate, was synthesized by Biosyntan GmbH, Berlin, Germany. Acetyl Coenzyme A was purchased from Sigma-Aldrich (#A-2056).Kat6a was incubated for 60 mins at 22° C. in the presence of different concentrations of test substances (0 μM, and within the range 0.01-20 μM) in assay buffer [25 mM Tris/HCl pH 8, 1 mM EGTA, 2.5 mM Glutathion, 0.02% Chicken Albumin, 0.05% Pluronic F127, 25 mM NaCl, 220 nM H4 peptide and 600 nM Acetyl Coenzym A].The reaction was stopped by addition of Detection Solution (25 mM HEPES pH 7.5, 0.1% BSA, 22 nM SAXL665 (Cisbio #610SAXLE), 100 μM Anacardic Acid (Enzo #ALX-270-381), 1 nM Anti-Histone H4 (ACETYL K8) Antibody (ABCAM #AB15823) and 0.5 nM Anti-Rabbit IgG Eu (Perkin Elmer #AD0083).
- Enzyme Inhibition Assay Enzyme inhibition studies were performed using recombinant JAK1 (amino acids 866-1154, Life Technologies, PV4774, Carlsbad, Calif.), JAK2 (amino acids 831-1132), or JAK3 (amino acids 781-1124) under buffer conditions of 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween 20, 50 μg/mL BSA, and 10 mM MgCl2. JAK enzyme was expressed as an N-terminal GST fusion in insect cells and purified by glutathione-affinity and size-exclusion chromatographies. Enzymes were assayed both at their respective ATP Km (JAK1: 55 μM, JAK2: 15 μM, JAK3: 3 μM) and the approximated high end of physiological ATP concentration of 5 mM, in the presence of inhibitor dosed at 30, 3, 0.3, 0.03, 0.003 and 0 μM final test concentrations. For JAK1, 6 nM of enzyme (for Km ATP assay) or 4 nM enzyme (for high ATP assay) was incubated with 1.5 μM peptide substrate (FITC-C6-KKHTDDGYMPMSPGVA-NH2 (SEQ ID NO:1)). For JAK2, 0.8 nM of enzyme (for Km ATP assay) or 0.3 nM enzyme (for high ATP assay) was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO:2)). For JAK3, 0.2 nM of enzyme (for Km ATP assay) or 0.1 nM enzyme (for high ATP assay) was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO:2), Intonation, Boston, Mass.).
- Human FXR (NR1H4) Assay The potency and efficacy of the compounds of the invention on TGR5 receptor was evaluated using in vitro assays which carried out using the express kit from DiscoverX (cAMP HUNTER eXpress GPBAR1 CHO-K1 GPCR Assay; Cataloguer number: 95-0049E2CP2S)GPBAR1 (G protein-coupled bile acid receptor 1) encodes a member of the G protein-coupled receptor (GPCR) superfamily. GPBAR1 activation following ligand binding initiates a series of second messenger cascades that result in a cellular response. Treatment of CHO cells expressing GPBAR1 with bile acids induces the production of intracellular cAMP and internalization of the receptor. The potency and efficacy of compound for GPBAR1 activation by measuring cyclic adenosine monophosphate (cyclic AMP or cAMP) levels in live cells using a competitive immunoassay based on Enzyme Fragment Complementation (EFC).In briefly, following seeding the cells into the white, 96 well microplate, place it in a 37° C., 5% CO2 in a humidified incubator for 18-24 hours prior to testing. On second day, proceed to the appropriate cAMP HUNTER eXpress Protocol according to the manufacturer's instructions. Dissolve agonist compound in DMSO at the desired stock concentration, and prepare 3-fold serial dilutions of agonist compound in Cell Assay Buffer. The concentration of each dilution should be prepared at 4× of the final screening concentration (i.e. 15 μL compound+45 μL Cell Assay Buffer/cAMP Antibody Reagent). For each dilution, the final concentration of solvent should remain constant. Transfer 15 μL diluted compound the assay plate and incubate the plate for 30 minutes at 37° C. Following agonist incubation, add 60 μL of working cAMP detection reagents/cAMP Solution mixture (cAMP Lysis Buffer, Substrate Reagent 1, cAMP Solution D) to the appropriate wells. Incubate for 1 hour at room temperature (23° C.), protected from light. Add 60 μl of cAMP Solution A to the appropriate wells. Incubate for 3 hours at room temperature (23° C.), protected from light. Read samples on Envision standard luminescence plate reader. Calculate of average EC50 after logarithm transformation.
- Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak1 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 8 μM Omnia Y12 peptide (Catalog # IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 5 nM Jak1 in a total volume of 20 μL. GST-tagged human Jak1 kinase domain comprising amino acids 866-1154 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV4774).
- Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak3 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 10 μM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 1.5 nM Jak3 in a total volume of 20 μL. GST-tagged human Jak3 kinase domain comprising amino acids 781-1124 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV3855).
- Jak1 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak1 using the general enzyme inhibition assay method, in which the assay mixture contained 50 μM ATP, 8 μM Omnia Y12 peptide (Catalog #IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 5 nM Jak1 in a total volume of 20 μL. GST-tagged human Jak1 kinase domain comprising amino acids 866-1154 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog #IVGN PV4774).
- Jak1 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak1 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 8 μM Omnia Y12 peptide (Catalog # IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 5 nM Jak1 in a total volume of 20 μL. GST-tagged human Jak1 kinase domain comprising amino acids 866-1154 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV4774).
- Jak2 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak2 using the general enzyme inhibition assay method, in which the assay mixture contained 50 μM ATP, 10 μM Omnia Y7 peptide (Catalog #IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 4 nM Jak2 in a total volume of 20 μL. Human Jak2 kinase domain comprising amino acids 808-1132 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog #IVGN PV4210).
- Jak2 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak2 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 10 μM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 4 nM Jak2 in a total volume of 20 μL. Human Jak2 kinase domain comprising amino acids 808-1132 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV4210).
- Jak3 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak3 using the general enzyme inhibition assay method, in which the assay mixture contained 50 μM ATP, 10 μM Omnia Y7 peptide (Catalog #IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 1.5 nM Jak3 in a total volume of 20 μL. GST-tagged human Jak3 kinase domain comprising amino acids 781-1124 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog #IVGN PV3855).
- Jak3 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Jak3 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 10 μM Omnia Y7 peptide (Catalog # IVGN KNZ3071C, Invitrogen Corporation, Carlsbad, Calif.) and 1.5 nM Jak3 in a total volume of 20 μL. GST-tagged human Jak3 kinase domain comprising amino acids 781-1124 was purchased from Invitrogen Corporation, Carlsbad, Calif. (catalog # IVGN PV3855).
- Enzyme Inhibition Assay Enzyme inhibition studies were performed using recombinant JAK1 (amino acids 866-1154, Life Technologies, #PV4774, Carlsbad, Calif.), JAK2 (amino acids 831-1132), or JAK3 (amino acids 781-1124) under buffer conditions of 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween 20, 50 μg/mL BSA, and 10 mM MgCl2. JAK enzyme was expressed as an N-terminal GST fusion in insect cells and purified by glutathione-affinity and size-exclusion chromatographies. Enzymes were assayed both at their respective ATP Km (JAK1: 55 μM, JAK2: 15 μM, JAK3: 3 μM) and the approximated high end of physiological ATP concentration of 5 mM, in the presence of inhibitor dosed at 30, 3, 0.3, 0.03, 0.003 and 0 μM final test concentrations. For JAK1, 6 nM of enzyme (for Km ATP assay) or 4 nM enzyme (for high ATP assay) was incubated with 1.5 μM peptide substrate (FITC-C6-KKHTDDGYMPMSPGVA-NH2 (SEQ ID NO:1), Intonation, Boston, Mass.). For JAK2, 0.8 nM of enzyme (for Km ATP assay) or 0.3 nM enzyme (for high ATP assay) was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO:2), Intonation, Boston, Mass.). For JAK3, 0.2 nM of enzyme (for Km ATP assay) or 0.1 nM enzyme (for high ATP assay) was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO:2), Intonation, Boston, Mass.). Phosphorylated and unphosphorylated peptides were separated and quantified by a Caliper LC3000 system (Caliper Life Sciences, MA) for calculating percent inhibition.
- PERK In Vitro Activity Assay In vitro Inhibition of PERK Enzyme Activity (isolated) Recombinant human EIF2AK2 (PKR) catalytic domain (amino acids 252-551), EIF2AK3 (PERK) catalytic domain (amino acids 536-1116), GFP-eIF2a substrate, and Terbium-labelled phospho-eIF2a antibody is obtained (Invitrogen, Carlsbad, CA).Express and purify HIS-SUMO-GCN2 catalytic domain (amino acids 584-1019) from E. coli. Perform TR-FRET kinase assays in the absence or presence of inhibitors in a reaction buffer consisting of 50 mM HEPES, pH 7.5, 10 mM MgCb, 1.0 mM EGTA, and 0.01% Brij-35, and 100-200 nM GFP-eIF2a substrate. PKR assays contain 14 ng/mL enzyme and 2.5 μM ATP (Km, −2.5 μM), PERK assays contain 62.5 ng/mL enzyme and 1.5 μM ATP (Km. app −1.5 uM), and GCN2 assays contain 3 nM enzyme and 90 μM ATP (Km, −200 uM). Add test compound, initiate the reaction by addition of enzyme, and incubate at room temperature for 45 minutes. Stop the reaction by addition of EDTA to a final concentration of 10 mM, add Terbium-labelled phospho-eIF2a antibody at a final concentration of 2 nM, and incubate for 90 minutes. Monitor the resulting fluorescence in an EnVison® Multilabel reader (PerkinElmer, Waltham, MA). Determine TR-FRET ratios and the resulting IC50 values using a 4-parameter nonlinear logistic equation as shown: Y=(A+((B−A)/(1+(C/x)AD)))) where, Y=% specific inhibition, A=Bottom of the curve, B=Top of the curve, C=absolute IC50 (concentration causing 50% inhibition), and D=hill slope.
- Alpha Screen Assay A biotin labeled peptide is used as substrate (amino acid sequence: Biotin-Glu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) SEQ ID NO: 1). FAK enzyme was expressed in insect cells as catalytic domain (amino acids 411-686) N-terminally tagged with six histidine amino acids and a Tobacco Etch Virus (TeV) cleavage sequence. After lysing the cells by sonication, the kinase was purified by Ni-Immobilised Metal Affinity Chromatography, TeV cleavage leaving a N-terminal glycine, and gel filtration. The 15 ul assay reactions are run in Greiner brand white 384-well low volume plates. All reactions contained 10 mM HEPES pH 7.4, 25 mM NaCI, 10 mM MgCl2, 0.01% (v/v) Tween-20, 50 uM Na3V04, 0.01% (w/v) albumin from chicken egg white, 111 nM peptide substrate, 80 pM ATP, and 4 ng/reaction FAK enzyme, with the enzyme being omitted from negative control reactions. Compounds were added in a volume of 100 nl from dilution series made up in DMSO.
- Biochemical Alpha Screen Assay A biotin labeled peptide is used as substrate (amino acid sequence: Biotin-Glu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2)1SEQ ID NO: 1). FAK enzyme was expressed in insect cells as catalytic domain (amino acids 411-686)N-terminally tagged with six histidine amino acids and a Tobacco Etch Virus (TeV) cleavage sequence. After lysing the cells by sonication, the kinase was purified by Ni-Immobilised Metal Affinity Chromatography chromatography, TeV cleavage leaving a N-terminal glycine, and gel filtration. The 15 ul assay reactions are run in Greiner brand white 384-well low volume plates. All reactions contained 10 mM HEPES pH 7.4, 25 mM NaCl, 10 mM MgCl2, 0.01% (v/v) Tween-20, 50 uM Na3V04, 0.01% (w/v) albumin from chicken egg white, 111 nM peptide substrate, 80 uM ATP, and 4 ng/reaction FAK enzyme, with the enzyme being omitted from negative control reactions. Compounds were added in a volume of 100 nl from dilution series made up in DMSO.
- Time Resolved Fluorescence Energy Transfer (TR-FRET) Assay The inhibition of p53-Hdm2 and p53-Hdm4 interactions is measured by time resolved fluorescence energy transfer (TR-FRET). Fluorescence energy transfer (or Foerster resonance energy transfer) describes an energy transfer between donor and acceptor fluorescent molecules. For this assay, MDM2 protein (amino acids 2-188) and MDM4 protein (amino acids 2-185), tagged with a C-terminal Biotin moiety, are used in combination with a Europium labeled streptavidin (Perkin Elmer, Inc., Waltham, Mass., USA) serving as the donor fluorophore. The p53 derived, Cy5 labeled peptide Cy5-TFSDLWKLL (p53 aa 18-26) is the energy acceptor. Upon excitation of the donor molecule at 340 nm, binding interaction between MDM2 or MDM4 and the p53 peptide induces energy transfer and enhanced response at the acceptor emission wavelength at 665 nm. Disruption of the formation of the p53-MDM2 or p53-MDM4 complex due to an inhibitor molecule binding to the p53 binding site of MDM2 or MDM4 results in increased donor emission.
- AlphaScreen Assay 20 nM ofGST-tagged HCNlc40 protein (corresponding to the C terminal 40 amino acids of HCN1) was incubated with 200 nM of His-tagged TRIP8b(241-602) and varying concentrations of the test compound as described in our prior report (Han et al., 2015). After a 3 h incubation, anti-GST AlphaScreen acceptor beads were added for 1.5 h followed by AlphaScreen nickel chelate donor beads for 1.5 h. AlphaScreen signal was quantified using a PerkinElmer (Waltham, MA) EnSpire multimode plate reader
- Inhibition Assay Tyk2: Compounds of Formula I were screened for their ability to inhibit Tyk2 using the general enzyme inhibition assay method, in which the assay mixture contained 500 μM ATP, 8 μM Omnia Y12 peptide (Catalog # IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 1 nM Tyk2 in a total volume of 20 μL. Human Tyk2 kinase domain, comprising amino acids 886 to 1187 with 10 additional histidine residues (histidine tag) on the carboxy terminus, was expressed and purified from bacculovirus.
- Fluorimetric Assay Inhibitory constants (Ki) and IC50 values were determined under saturating substrate conditions by using a fluorimetric assay (components were purchased separately). This assay system allows detection of a fluorescent signal upon SIRT6 deacetylation of the fluorescent substrate peptide (AMC-p53) with amino acids 379-382 (Arg-His-Lys-LysAc). Sirtuin deacetylation of the substrate renders the fluorophore-substrate bond susceptible to treatment with lysyl endopeptidase. Trypsin cleavage releases the fluorophore, resulting in an increase in fluorescence. Fluorescence intensity was measured on a Synergy HT Multi-Mode microplate fluorescence reader.
- Spectrophotometric 384 Well Assay Malonyl CoA formation by acetyl CoA carboxylases is stoichometrically linked to the consumption of ATP. ACC2 activity is measured in a NADH-linked kinetic method measuring ADP generated during the ACC reaction using a coupled lactate dehydrogenase/pyruvate kinase reaction. For biological testing, a human ACC2 construct which lacks the 128 amino acids at the N-terminus for increased solubility (nt 385-6966 in Genbank entry AJ575592) is cloned. The protein is then expressed in insect cells using a baculoviral expression system. Protein purification is performed by anion exchange.
- Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay Test Example 2: Potency of compounds were also measured using another fluorogenic substrate, TruPoint BACE1 Substrate Eu-CEVNLDAEFK-QSY 7 (SEQ ID NO:3) (AD0258, PerkinElmer, Boston Mass.). This substrate also has Swedish variant amino acids at the β-secretase cleavage site, with a fluorescent europium (Eu) chelate coupled to one end and a quencher of europium fluorescence (QSY7) coupled to the other end via lysine. If the sample contains BACE1 activity, the Eu chelate and the quencher will be separated as the substrate is cleaved.
- Tyk2 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Tyk2 using the general enzyme inhibition assay method, in which the assay mixture contained 50 μM ATP, 8 μM Omnia Y12 peptide (Catalog #IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 1 nM Tyk2 in a total volume of 20 μL. Human Tyk2 kinase domain, comprising amino acids 886 to 1187 with 10 additional histidine residues (histidine tag) on the carboxy terminus, was expressed and purified from bacculovirus in-house at Array BioPharma Inc. (Boulder, Colo.).
- Tyk2 Inhibition Assay Compounds of Formula I were screened for their ability to inhibit Tyk2 using the general enzyme inhibition assay method, in which the assay mixture contained 500 uM ATP, 8 uM Omnia Y12 peptide (Catalog # IVGN KPZ3121C; Invitrogen Corporation, Carlsbad, Calif.) and 1 nM Tyk2 in a total volume of 20 uL. Human Tyk2 kinase domain, comprising amino acids 886 to 1187 with 10 additional histidine residues (histidine tag) on the carboxy terminus, was expressed and purified from baculovirus in-house at Array BioPharma Inc. (Boulder, Colo.).
- Urease Inhibition Assay The inhibition studies of soybean urease were initiated with boric acid and boronic acids (butylboronic acid, 4-bromophenylboronic acid, and phenylboronic acid). Also, heavy metal ions (HgCl2, AgCl, and Cu(CH3COO)2) and sodium salts of mineral acids (NaF, NaCl, NaNO3, and Na2SO4) were investigated for their inhibitory effects. Stock solutions of inhibitors, except for 4-bromophenylboronicacid, were prepared in 0.05 M Tris-acetate buffer, pH 7.0, and were suitably diluted for experiments, whereas a stock solution of 4-bromophenylboronic acid was prepared in absolute ethanol and subsequently diluted in respective buffer. The activity assay was carried out at standard conditions as described earlier in the presence of varying concentrations of inhibitors. The yellow-orange colored solution was measured at 405 nm on a Unicam UV-2 spectrophotometer. The amount of NH3 liberated in the reaction mixture was estimated by calibrating Nessler's reagent with standard NH4Cl solution. One enzyme unit is defined as the amount of urease required to liberate 1 μmol of ammonia per minute under our test conditions (0.1 M urea, 0.05 M Trisacetatebuffer, pH 7.0, 37°C).