lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc2cnn(Cc3ncc(C4CC5(C4)CN(C4CCOCC4)C5)cc3OC)c12
InChIKey: DWENRDOMYMNPMQ-NRFANRHFSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin) using BFC as substrate preincubated with compound followed by substrate addition at 5 mins
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 550.71, ALogP 3.18, HBA 11, HBD 3, PSA 136.47, QED 0.33
Compound (SMILES): O=C1NC(N[C@@H]2CN3CCC2CC3)=N/C1=C\c1ccc2ncsc2c1
InChIKey: CBTNARFZVOPLBO-XIEDVDOYSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 483 nM (pChEMBL 6.320000171661377)
Descriptors: MW 353.45, ALogP 1.81, HBA 6, HBD 2, PSA 69.62, QED 0.81
Compound (SMILES): COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(C(F)(F)F)n3)CC2)CC1
InChIKey: UUBRCCCOMNXSPK-IYARVYRRSA-N
Target: 5-hydroxytryptamine receptor 2A (SINGLE PROTEIN), Homo sapiens
UniProt: P28223
Assay: Displacement of [3H]-5-HT from 5HT2A receptor in HEK293 cell membranes by scintillation counting method
Measurement: Ki = 4420 nM (pChEMBL 5.360000133514404)
Descriptors: MW 442.53, ALogP 3.32, HBA 5, HBD 1, PSA 57.7, QED 0.67
Compound (SMILES): Cc1csc(CNC2=N/C(=C\c3ccc4ncsc4c3)C(=O)N2)n1
InChIKey: YYSXUOHHBBMQMJ-QCDXTXTGSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 1803 nM (pChEMBL 5.739999771118164)
Descriptors: MW 355.45, ALogP 2.68, HBA 7, HBD 2, PSA 79.27, QED 0.71
Compound (SMILES): O=C1NC(NCc2ccncc2)=N/C1=C\c1ccc2ncsc2c1
InChIKey: MVRRAWJPZXNFMK-AUWJEWJLSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 1030 nM (pChEMBL 5.989999771118164)
Descriptors: MW 335.39, ALogP 2.31, HBA 6, HBD 2, PSA 79.27, QED 0.72
Compound (SMILES): Cc1ccc(NC2=N/C(=C\c3ccc4ncsc4c3)C(=O)N2)cc1F
InChIKey: NRHKUKQUEJSGMG-UUASQNMZSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 3058 nM (pChEMBL 5.510000228881836)
Descriptors: MW 352.39, ALogP 3.68, HBA 5, HBD 2, PSA 66.38, QED 0.69
Compound (SMILES): O=C1NC(NC2CC23CCCCC3)=N/C1=C\c1ccc2ncsc2c1
InChIKey: ROPFCXUWNMYMSW-ZSOIEALJSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 343 nM (pChEMBL 6.460000038146973)
Descriptors: MW 352.46, ALogP 3.44, HBA 5, HBD 2, PSA 66.38, QED 0.81
Compound (SMILES): COC(=O)[C@H](Cc1ccccc1)NC1=N/C(=C\c2ccc3ncsc3c2)C(=O)N1
InChIKey: WQYUNADCLFWKGN-RNIVLKNTSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 2160 nM (pChEMBL 5.670000076293945)
Descriptors: MW 406.47, ALogP 2.5, HBA 7, HBD 2, PSA 92.68, QED 0.5
Compound (SMILES): CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(-c4noc(CN5CCCNCC5)n4)cc3OC)nc2N1C1CCCC1
InChIKey: XSTRJMHOLBBWNN-JOCHJYFZSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of human ERG transfected in CHO cells by patch-clamp method
Measurement: IC50 = 2010 nM (pChEMBL 5.699999809265137)
Descriptors: MW 561.69, ALogP 3.58, HBA 11, HBD 2, PSA 124.78, QED 0.42
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc2cnn(Cc3ncc(C4CCN(C5CCOCC5)CC4)cc3OC)c12
InChIKey: RZRJLAWKPZNKQG-NRFANRHFSA-N
Target: Cytochrome P450 2C8 (SINGLE PROTEIN), Homo sapiens
UniProt: P10632
Assay: Inhibition of CYP2C8 (unknown origin)
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 538.7, ALogP 3.18, HBA 11, HBD 3, PSA 136.47, QED 0.33
Compound (SMILES): O=C1NC(N[C@@H](CO)Cc2ccccc2)=N/C1=C\c1ccc2ncsc2c1
InChIKey: HAFFBDGNUZMNIJ-GESOSKEOSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 4262 nM (pChEMBL 5.369999885559082)
Descriptors: MW 378.46, ALogP 2.32, HBA 6, HBD 3, PSA 86.61, QED 0.59
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@@H]1CCCN/C(N)=N/C(=O)NCCCCNC(=O)[C@H](N)CC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F
InChIKey: JPOOIPCJAFXCKZ-DIBFXYFISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4R expressed in CHO cells co-expressing Gqi5-mtAEQ by calcium2+ aequorin assay
Measurement: EC50 = 8 nM (pChEMBL 8.100000381469727)
Descriptors: MW 1136.33
Compound (SMILES): C[C@]12CC3CC(NC4=N/C(=C\c5ccc6ncsc6c5)C(=O)N4)(C1)C[C@@](C)(C3)C2
InChIKey: FVIUKIZPDJZQKD-LARPSKPRSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O43781
Assay: Inhibition of human DYRK3 using RBERIRStide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 1160 nM (pChEMBL 5.940000057220459)
Descriptors: MW 406.56, ALogP 4.46, HBA 5, HBD 2, PSA 66.38, QED 0.72
Compound (SMILES): Cn1cncc1C1=CN(c2ncnc3[nH]cnc23)CCS1
InChIKey: IEDDDZFQZKDRBJ-UHFFFAOYSA-N
Target: cAMP-dependent protein kinase catalytic subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P17612
Assay: Inhibition of PKAc alpha (unknown origin)
Measurement: IC50 = 84 nM (pChEMBL 7.079999923706055)
Descriptors: MW 299.36, ALogP 1.64, HBA 7, HBD 1, PSA 75.52, QED 0.78
Compound (SMILES): CC(=O)N1CCc2ccc(NC3=N/C(=C\c4ccc5ncsc5c4)C(=O)N3)cc21
InChIKey: HGMCNIGKEVZHFM-IUXPMGMMSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 705 nM (pChEMBL 6.150000095367432)
Descriptors: MW 403.47, ALogP 3.14, HBA 6, HBD 2, PSA 86.69, QED 0.64
Compound (SMILES): O=C1NC(NC23CC4CC(CC(C4)C2)C3)=N/C1=C\c1ccc2nnsc2c1
InChIKey: WWRVEMKSOIGGCS-SOFYXZRVSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 379.49, ALogP 3.08, HBA 6, HBD 2, PSA 79.27, QED 0.79
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc2cnn(Cc3ncc(C4CC5(C4)CN(C4CCOCC4)C5)cc3OC)c12
InChIKey: DWENRDOMYMNPMQ-NRFANRHFSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin) using BFC as substrate preincubated with compound followed by substrate addition at 30 mins
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 550.71, ALogP 3.18, HBA 11, HBD 3, PSA 136.47, QED 0.33
Compound (SMILES): O=C1NC(N[C@@H]2CN3CCC2CC3)=N/C1=C\c1ccc2ncsc2c1
InChIKey: CBTNARFZVOPLBO-XIEDVDOYSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 353.45, ALogP 1.81, HBA 6, HBD 2, PSA 69.62, QED 0.81
Compound (SMILES): COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(C(F)(F)F)n3)CC2)CC1
InChIKey: UUBRCCCOMNXSPK-IYARVYRRSA-N
Target: 5-hydroxytryptamine receptor 2B (SINGLE PROTEIN), Homo sapiens
UniProt: P41595
Assay: Displacement of [3H]-5-HT from 5HT2B receptor in HEK293 cell membranes by scintillation counting method
Measurement: Ki = 11.3 nM (pChEMBL 7.949999809265137)
Descriptors: MW 442.53, ALogP 3.32, HBA 5, HBD 1, PSA 57.7, QED 0.67
Compound (SMILES): Cc1csc(CNC2=N/C(=C\c3ccc4ncsc4c3)C(=O)N2)n1
InChIKey: YYSXUOHHBBMQMJ-QCDXTXTGSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 954 nM (pChEMBL 6.019999980926514)
Descriptors: MW 355.45, ALogP 2.68, HBA 7, HBD 2, PSA 79.27, QED 0.71
Compound (SMILES): O=C1NC(NCc2ccncc2)=N/C1=C\c1ccc2ncsc2c1
InChIKey: MVRRAWJPZXNFMK-AUWJEWJLSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 1241 nM (pChEMBL 5.909999847412109)
Descriptors: MW 335.39, ALogP 2.31, HBA 6, HBD 2, PSA 79.27, QED 0.72
Compound (SMILES): Cc1ccc(NC2=N/C(=C\c3ccc4ncsc4c3)C(=O)N2)cc1F
InChIKey: NRHKUKQUEJSGMG-UUASQNMZSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 352.39, ALogP 3.68, HBA 5, HBD 2, PSA 66.38, QED 0.69
Compound (SMILES): O=C1NC(NC2CC23CCCCC3)=N/C1=C\c1ccc2ncsc2c1
InChIKey: ROPFCXUWNMYMSW-ZSOIEALJSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 938 nM (pChEMBL 6.03000020980835)
Descriptors: MW 352.46, ALogP 3.44, HBA 5, HBD 2, PSA 66.38, QED 0.81
Compound (SMILES): COC(=O)[C@H](Cc1ccccc1)NC1=N/C(=C\c2ccc3ncsc3c2)C(=O)N1
InChIKey: WQYUNADCLFWKGN-RNIVLKNTSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 445 nM (pChEMBL 6.349999904632568)
Descriptors: MW 406.47, ALogP 2.5, HBA 7, HBD 2, PSA 92.68, QED 0.5
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc2cnn(Cc3ncc(C4CCN(C5CCOCC5)CC4)cc3OC)c12
InChIKey: RZRJLAWKPZNKQG-NRFANRHFSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin) using BFC as substrate preincubated with compound followed by substrate addition at 5 mins
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 538.7, ALogP 3.18, HBA 11, HBD 3, PSA 136.47, QED 0.33
Compound (SMILES): O=C1NC(N[C@@H](CO)Cc2ccccc2)=N/C1=C\c1ccc2ncsc2c1
InChIKey: HAFFBDGNUZMNIJ-GESOSKEOSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 1146 nM (pChEMBL 5.940000057220459)
Descriptors: MW 378.46, ALogP 2.32, HBA 6, HBD 3, PSA 86.61, QED 0.59
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@@H]1CCCN/C(N)=N/C(=O)NCCCCNC(=O)[C@H](N)CC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F
InChIKey: JPOOIPCJAFXCKZ-DIBFXYFISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4R expressed in HEK293T cells by miniGsi assay
Measurement: EC50 = 1.096 nM (pChEMBL 8.960000038146973)
Descriptors: MW 1136.33
Compound (SMILES): C[C@]12CC3CC(NC4=N/C(=C\c5ccc6ncsc6c5)C(=O)N4)(C1)C[C@@](C)(C3)C2
InChIKey: FVIUKIZPDJZQKD-LARPSKPRSA-N
Target: Dual specificity tyrosine-phosphorylation-regulated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR20
Assay: Inhibition of human DYRK4 using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 2129 nM (pChEMBL 5.670000076293945)
Descriptors: MW 406.56, ALogP 4.46, HBA 5, HBD 2, PSA 66.38, QED 0.72
Compound (SMILES): CC(=O)N1CCc2ccc(NC3=N/C(=C\c4ccc5ncsc5c4)C(=O)N3)cc21
InChIKey: HGMCNIGKEVZHFM-IUXPMGMMSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 1831 nM (pChEMBL 5.739999771118164)
Descriptors: MW 403.47, ALogP 3.14, HBA 6, HBD 2, PSA 86.69, QED 0.64
Compound (SMILES): O=C1NC(NC23CC4CC(CC(C4)C2)C3)=N/C1=C\c1ccc2nnsc2c1
InChIKey: WWRVEMKSOIGGCS-SOFYXZRVSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 379.49, ALogP 3.08, HBA 6, HBD 2, PSA 79.27, QED 0.79
Compound (SMILES): O=C1NC(N[C@@H]2CN3CCC2CC3)=N/C1=C\c1ccc2ncsc2c1
InChIKey: CBTNARFZVOPLBO-XIEDVDOYSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 353.45, ALogP 1.81, HBA 6, HBD 2, PSA 69.62, QED 0.81
Compound (SMILES): COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(C(F)(F)F)n3)CC2)CC1
InChIKey: UUBRCCCOMNXSPK-IYARVYRRSA-N
Target: 5-hydroxytryptamine receptor 2C (SINGLE PROTEIN), Homo sapiens
UniProt: P28335
Assay: Displacement of [3H]-5-HT from 5HT2C receptor in HEK293 cell membranes by scintillation counting method
Measurement: Ki = 3170 nM (pChEMBL 5.5)
Descriptors: MW 442.53, ALogP 3.32, HBA 5, HBD 1, PSA 57.7, QED 0.67
Compound (SMILES): Cc1csc(CNC2=N/C(=C\c3ccc4ncsc4c3)C(=O)N2)n1
InChIKey: YYSXUOHHBBMQMJ-QCDXTXTGSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 2155 nM (pChEMBL 5.670000076293945)
Descriptors: MW 355.45, ALogP 2.68, HBA 7, HBD 2, PSA 79.27, QED 0.71
Compound (SMILES): O=C1NC(NCc2ccncc2)=N/C1=C\c1ccc2ncsc2c1
InChIKey: MVRRAWJPZXNFMK-AUWJEWJLSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 3255 nM (pChEMBL 5.489999771118164)
Descriptors: MW 335.39, ALogP 2.31, HBA 6, HBD 2, PSA 79.27, QED 0.72
Compound (SMILES): Cc1ccc(NC2=N/C(=C\c3ccc4ncsc4c3)C(=O)N2)cc1F
InChIKey: NRHKUKQUEJSGMG-UUASQNMZSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 352.39, ALogP 3.68, HBA 5, HBD 2, PSA 66.38, QED 0.69
Compound (SMILES): O=C1NC(NC2CC23CCCCC3)=N/C1=C\c1ccc2ncsc2c1
InChIKey: ROPFCXUWNMYMSW-ZSOIEALJSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 854 nM (pChEMBL 6.070000171661377)
Descriptors: MW 352.46, ALogP 3.44, HBA 5, HBD 2, PSA 66.38, QED 0.81
Compound (SMILES): COC(=O)[C@H](Cc1ccccc1)NC1=N/C(=C\c2ccc3ncsc3c2)C(=O)N1
InChIKey: WQYUNADCLFWKGN-RNIVLKNTSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 406.47, ALogP 2.5, HBA 7, HBD 2, PSA 92.68, QED 0.5
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc2cnn(Cc3ncc(C4CCN(C5CCOCC5)CC4)cc3OC)c12
InChIKey: RZRJLAWKPZNKQG-NRFANRHFSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin) using BFC as substrate preincubated with compound followed by substrate addition at 30 mins
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 538.7, ALogP 3.18, HBA 11, HBD 3, PSA 136.47, QED 0.33
Compound (SMILES): O=C1NC(N[C@@H](CO)Cc2ccccc2)=N/C1=C\c1ccc2ncsc2c1
InChIKey: HAFFBDGNUZMNIJ-GESOSKEOSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 2743 nM (pChEMBL 5.559999942779541)
Descriptors: MW 378.46, ALogP 2.32, HBA 6, HBD 3, PSA 86.61, QED 0.59
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@@H]1CCCN/C(N)=N/C(=O)NCCCCNC(=O)[C@H](N)CC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F
InChIKey: JPOOIPCJAFXCKZ-DIBFXYFISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4R expressed in HEK293T cells by miniGsi assay
Measurement: EC50 = 1.1 nM (pChEMBL 8.960000038146973)
Descriptors: MW 1136.33
Compound (SMILES): C[C@]12CC3CC(NC4=N/C(=C\c5ccc6ncsc6c5)C(=O)N4)(C1)C[C@@](C)(C3)C2
InChIKey: FVIUKIZPDJZQKD-LARPSKPRSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of N-terminal GST/His6-fused human full length GSK-3-beta (1 to 420 residues) expressed in Sf9 cells using RBERCHKtide and [gamma33P]ATP as substrate incubated for 60 mins by radiometric 33PanQinase assay
Measurement: IC50 = 2787 nM (pChEMBL 5.550000190734863)
Descriptors: MW 406.56, ALogP 4.46, HBA 5, HBD 2, PSA 66.38, QED 0.72
Compound (SMILES): CCCCCCCCCCCCCCCCOCCCOP(=O)(O)COc1ccc2c(C(C)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
InChIKey: RYWFHTSVWNBCNR-OCUJDILZSA-N
Target: Complement factor D (SINGLE PROTEIN), Homo sapiens
UniProt: P00746
Assay: Enzyme Assay: Human factor D (purified from human serum, Complement Technology, Inc.) at 80 nM final concentration is incubated with test compound at various concentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl, pH 7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman's reagent) are added to final concentrations of 100 M each. The increase in color is recorded at OD405 nm in a microplate in kinetic mode over 30 minutes with 30 second time points in a spectrofluorimeter. IC50 values are calculated by non-linear regression from the percentage of inhibition of complement factor D activity as a function of test compound concentration.
Measurement: IC50 < 1000 nM (pChEMBL 6)
Descriptors: MW 866.42, ALogP 10.32, HBA 8, HBD 2, PSA 136.4, QED 0.04
Compound (SMILES): NC[C@@H](O)CNS(=O)(=O)c1ccc(Nc2ncc[nH]2)c(-c2nn[nH]n2)c1S(N)(=O)=O
InChIKey: OLXIFPYVDJEZDB-SSDOTTSWSA-N
Target: Metallo-beta-lactamase type 2 (SINGLE PROTEIN), Bacteria
UniProt: C7C422
Assay: Enzyme Activity: Determination of IC50 : The Class B enzyme activities were measured in the presence of the test inhibitor in a fluorescence assay against a commercially available substrate consisting of a cephalosporin core linking 7-hydroxycoumarin to fluorescein (CCF2-FA). The enzyme (NDM-1, IMP-1 or VIM-1) and the substrate were diluted in 100 mM KH2PO4 buffer (pH 7) containing 0.005% Tween-20 and 10 μM ZnSO4. In the assay, the final concentration of enzyme was 1 pM, 2 pM and 30 pM for NDM-1, IMP-1 and VIM-1, respectively, and the final concentration of CCF2-FA was 1.25 μM. The test inhibitor was dissolved in dimethylsulfoxide and diluted 1:50 in the assay, resulting in a final concentration range of 20 μM to 0.00063 μM. In a 384-well microplate, the test inhibitor was incubated with the metallo-β-lactamase enzyme and the substrate for 2 hours at 25° C. Fluorescence at 460 nm following excitation at 405 nm was measured. The IC50 value was determined from semi-logarithmic plots of enzyme inhibition versus inhibitor concentration, with a curve generated using a 4-parameter fit.
Measurement: IC50 = 10.8 nM (pChEMBL 7.96999979019165)
Descriptors: MW 458.49, ALogP -2.42, HBA 11, HBD 7, PSA 247.75, QED 0.18
Compound (SMILES): O=C(Nc1cccc(-c2nc(NC(P(=O)(O)O)P(=O)(O)O)c3ccsc3n2)c1)C1CC1
InChIKey: JODOGELIBVRUMF-UHFFFAOYSA-N
Target: Geranylgeranyl pyrophosphate synthase (SINGLE PROTEIN), Homo sapiens
UniProt: O95749
Assay: In Vitro hGGPPS Inhibition Assay: The assay was based on a literature procedure (Kavanagh, et al. J. Biol. Chem., 2006, 281, 22004-22012) with minor modifications. All assays were run in triplicate using recombinant human GGPPS (80 ng), FPP (10 μM), IPP (8.3 μM; 3H-IPP, 40 mCi/mmoL) in a final volume of 100 μL buffer containing 50 mM Tris pH 7.7, 2 mM MgCl2, 1 mM TCEP, 5 μg/mL BSA and 0.2% (w/v) Tween 20. The enzyme and test compound were pre-incubated in the assay buffer in a volume of 80 μL at 37° C. for 10 mins. Afterwards, the substrates (FPP, IPP) were added to start the reaction, which also bring the compound, substrate, and buffer contents to the desired final concentrations as indicated above. The assay mixture was then incubated at 37° C. for 15 mins (Note: the incubation time is based from the curve determined each time a new batch of enzyme is produced). Assays were terminated by the addition of 200 μL of HCl/MeOH (1:4) and incubated for 10 min at 37° C. The mixture was then extracted with 700 μL of petroleum ether, dried through a plug of anhydrous Mg2SO4 and 300 μL of the dried ligroin phase was combined with 8 mL of scintillation cocktail. Finally, the radioactivity was counted using a Beckman Coulter LS6500 liquid scintillation counter.
Measurement: IC50 = 2550 nM (pChEMBL 5.590000152587891)
Descriptors: MW 484.37, ALogP 2.76, HBA 7, HBD 6, PSA 181.97, QED 0.27
Compound (SMILES): Cc1cc(C=O)nnc1-n1cnnn1
InChIKey: MIOSVPYYPHUWJB-UHFFFAOYSA-N
Target: ATP-sensitive inward rectifier potassium channel 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P48048
Assay: Thallium Flux Assay: A Thallium Flux Assay was performed on each of the final product compounds of the Examples. This assay has been described previously; see, e.g., PCT Published Application WO 2013/062900.
Measurement: IC50 = 24 nM (pChEMBL 7.619999885559082)
Descriptors: MW 190.17, ALogP -0.43, HBA 7, HBD 0, PSA 86.45, QED 0.6
Compound (SMILES): Cc1cc(C2CN(C(=O)c3cn4ccccc4n3)CC(F)(F)C2)n2ncnc2n1
InChIKey: CBKBCOKPJOLXEE-UHFFFAOYSA-N
Target: cGMP-dependent 3',5'-cyclic phosphodiesterase (SINGLE PROTEIN), Homo sapiens
UniProt: O00408
Assay: Enzymatic Assay: An IMAP TR-FRET-based phosphodiesterase assay was developed using the PDE2A isoform. IMAP technology is based on high-affinity binding of phosphate by immobilized metal (MIII) coordination complexes on nanoparticles. The IMAP binding reagent recognizes phosphate groups on AMP or GMP generated from cAMP or cGMP in a PDE reaction. Cyclic nucleotides that carry a phosphodiester bond and not a free phosphate are not recognized by the binding reagent. The time resolved fluorescence resonance energy transfer (TR-FRET) is afforded by a Terbium (Tb)-Donor pre-bound to the nanoparticles. FRET occurs when the fluorescent-labeled AMP or GMP product of a PDE reaction binds and comes into close proximity to the Tb-Donor complex. Due to the long lifetime of Tb fluorescence, detection can be run in time-resolved mode to reduce or eliminate interference from auto-fluorescent compounds.The IMAP TR-FRET PDE2A assay was performed in 1536-well white plates. A total of 250 pg per well of FLAG-tagged PDE2A1 (amino acids 2-941) was dispensed in 2.5 μL IMAP assay buffer consisting of 10 mM Tris pH 7.2, 10 mM MgCl2, 1 mM DTT, and 0.1% fatty acid free BSA. 30 nL of compound was then added from 1 mM stocks in DMSO using a Kalypsys Pintool. Plates were incubated for 5 min at room temperature before dispensing 1.5 μL of 533 nM FAM-cAMP substrate for a final concentration of 200 nM. Following a brief centrifugation, plates were incubated for 30 min at room temperature. The assay was terminated by adding 5 μL IMAP binding reagent Tb complex to each well which was prepared according to manufacturer's recommendations (Molecular Devices). Plates were incubated an additional 90 minutes at room temperature and read on a Viewlux plate reader. All compounds were solvated at a concentration of 10 mM in DMSO and tested in 11-point half-log dose-response. Curve fitting and IC50 values were determined using a standard four parameter fit.PDE2
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 397.39, ALogP 2.35, HBA 7, HBD 0, PSA 80.69, QED 0.52
Compound (SMILES): Oc1ccc2c(c1)C(c1ccc(O[C@H]3CCN(CCCF)C3)cc1)=C(c1ccc3[nH]ccc3c1)CCC2
InChIKey: MYSRFUNSXFGPNW-NDEPHWFRSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Estrogen Receptor Coactivator Assay: It is a competition assay, where binding of a test compound to a complex comprised of (i) His6-ERα298-554 protein representing ERα ligand-binding domain, (ii) Tb-labeled His6 antibody, (iii) a fluorescein-labeled PGC1α coactivator peptide (EAEEPSLLKKLLLAPANTQ), and (iv) estradiol, results in a decrease of the TR-FRET signal due to dissociation of the coactivator peptide. His6-ERα298-554 proteins were expressed as WT or D538G or Y537S mutants in E. coli and purified by affinity chromatography. The assay works in a homogeneous mix-and-read format. In a typical experiment, a 4 μL mixture of 0.5 nM His6-ERα298-554, 0.5 nM Tb-labeled His6 antibody, 250 nM PGC1a peptide, and 3 nM estradiol in 100 mM potassium phosphate, pH 7.4, 0.01% Tween-20, 0.02% NaN3, 5 mM DTT, was added to 40 nL test compound in DMSO and incubated overnight at room temperature. The TR-FRET 520:495 nm emission ratio was calculated and used to determine the IC50 value from a dose response curve fit to the 4-parameter logistic equation. The antagonist activity with respect to estrogen receptors in this test is given by the concentration which inhibits 50% of the estrogen receptor activity (or IC50) in nM.
Measurement: IC50 = 37 nM (pChEMBL 7.429999828338623)
Descriptors: MW 496.63, ALogP 6.98, HBA 3, HBD 2, PSA 48.49, QED 0.29
Compound (SMILES): CC(NC(=O)c1ccc(-c2ccncc2)cc1)c1cccc(OCC(=O)NC2CC2)c1
InChIKey: MUOZUQFVEHPKMK-UHFFFAOYSA-N
Target: Rho-associated protein kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75116
Assay: Kinase Inhibition Assay: The following assay protocol is for measuring the phosphorylation of a peptide substrate (FAM-KKLRRTLSVA-OH wherein FAM is carboxyfluorescein). The peptide is >98% purity by Capillary Electrophoresis. The peptide is phosphorylated by the protein kinase ROCK1 or ROCK2. The ROCK1 or ROCK2 enzyme, substrate, and cofactors (ATP and Mg2+) are combined in a well of a microtiter plate and incubated for 3 hours at 25° C. in the presence or absence of an inhibitor compound. At the end of the incubation, the reaction is quenched by the addition of an EDTA-containing buffer. The substrate and product are separated and quantified electrophoretically using the microfluidic-based LABCHIP® 3000 Drug Discovery System from Caliper Life Sciences (Hopkinton, Mass.).The components of the assay mixture are:100 mM HEPES, pH 7.50.1% BSA0.01% Triton X-1001 mM DTT10 mM MgCl210 μM Sodium Orthovanadate10 LM Beta-Glycerophosphate5 μM ATP (for ROCK1) or 7 μM ATP (for ROCK2)1% DMSO (from compound)1.25 μM FAM-KKLRRTLSVA-OH3 nM ROCK1 or 2.5 nM ROCK2 enzymeSubstrate and product peptides present in each sample are separated electrophoretically using the LABCHIP® 3000 capillary electrophoresis instrument. As substrate and product peptides are separated two peaks of fluorescence are observed. Change in the relative fluorescence intensity of the substrate and product peaks is the parameter measured reflecting enzyme activity. Capillary electrophoregramms (RDA acquisition files) are analyzed using HTS Well Analyzer software (Caliper Life Sciences, Hopkinton, Mass.). The kinase activity in each sample is determined as the product to sum ratio (PSR): P/(S+P), where P is the peak height of the product peptide and S is the peak height of the substrate peptide. For each compound, enzyme activity is measured at various concentrations (12 concentrations of compound spaced by 3× dilution intervals).
Measurement: IC50 = 9 nM (pChEMBL 8.050000190734863)
Descriptors: MW 415.49, ALogP 3.9, HBA 4, HBD 2, PSA 80.32, QED 0.58
Compound (SMILES): CC(C)c1ccccc1-c1ncc2c(n1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)C2
InChIKey: AHFWKLCLBKWQNW-UHFFFAOYSA-N
Target: Ubiquitin carboxyl-terminal hydrolase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: O94782
Assay: HTS Assay: The HTS assay was performed in a final volume of 20 μL in assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), 2 mM CaCl2) (1M Calcium Chloride solution; Sigma #21114) 1 mM GSH (L-Glutathione reduced; Sigma #G4251), 0.01% Prionex (0.22 μM filtered, Sigma #G-0411), and 0.01% Triton X-100. Stock compound solutions were stored at −20° C. as 10 mM in DMSO. Up to 1 month prior to the assay, 2 mM test compounds were pre-dispensed into assay plates (Black, low volume; Corning #3820) and frozen at −20° C. Prestamped assay plates were allowed to come to room temperature on the day of the assay. For the screen, 100 nL of 2 mM was pre-dispensed for a final screening concentration of 10 μM (DMSO(fc)=0.5%). The final concentration of the enzyme (USP1, construct USP1 (I-785, GG670, 671AA)/UAF1 (I-677)-Flag; Viva) in the assay was 100 μM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555) concentration was 25 nM with [Ub-Rh110]<<Km. 10 μL of 2× enzyme was added to assay plates (pre-stamped with compound) either simultaneously with 2×Ub-Rh110 or preincubated with USP1 40 minutes prior to the addition of 10 μL of 2×Ub-Rh110 to compound plates. Plates were incubated stacked for 45 minutes at room temperature before fluorescence was read on the Envision (Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on the PheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 440.55, ALogP 4.59, HBA 4, HBD 0, PSA 66.4, QED 0.58
Compound (SMILES): CNS(=O)(=O)CC1CCC(Nc2ncnc3sccc23)CC1
InChIKey: WHEUUGUIIPIVAD-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Caliper mobility shift assay: All four kinases of the JAK/TYK-kinase family were used as purified recombinant GST-fusion proteins, containing the active kinase domains. GST-JAK1(866-1154), GST-JAK3(811-1124), and GST-TYK2(888-1187) were expressed and purified by affinity chromatography at the EPK biology unit.The kinase assays were based on the Caliper mobility shift assay using the LabChip 3000 systems. This technology is similar to capillary electrophoresis and uses charge driven separation of substrate and product in a microfluidic chip.All kinase reactions were performed in 384 well microtiter plates in a total reaction volume of18 μI. The assay plates were prepared with 0.1 μl per well of test compound in the appropriate test concentration, as described under the section 'preparation of compound dilutions'. The reactions were started by combining 9 μl of substrate mix (consisting of peptide and ATP) with 9 μl of kinase dilution. The reactions were incubated for 60 minutes at 30° C. and stopped by adding 70 μl of stop buffer (100 mM Hepes, 5% DMSO, 0.1% Coating reagent, 10 mM EDTA, 0.015% Brij 35).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 340.47, ALogP 2.21, HBA 6, HBD 2, PSA 83.98, QED 0.87
Compound (SMILES): CC(C)COc1ccc(CCOC(=O)N(Cc2ccc(F)cc2)[C@H]2CCN(C)C[C@H]2F)cc1
InChIKey: JEZFZYPMSITVPJ-RPBOFIJWSA-N
Target: 5-hydroxytryptamine receptor 2A (SINGLE PROTEIN), Homo sapiens
UniProt: P28223
Assay: Receptor Selection and Amplification (R-SAT) Assays: R-SAT's were generally performed with 50 ng/well of receptor and 20 ng/well of β-galactosidase plasmid DNA. All receptor constructs used were in the pSI mammalian expression vector (Promega Inc) as described previously. The 5-HT2A receptor gene was amplified by nested PCR (polymerase chain reaction) from brain cDNA using the oligodcoxynuclcotides based on the published sequence (Saltzman et al., Biochem. Biophys. Res. Comm. 1991, 181, 1469). For large-scale transfections, cells were transfected for 12-16 h, then trypsinized and frozen in DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cells per well of a 96 well plate that contained a compound according to Formula (I). To run functional antagonist assays, cells and compounds were additionally combined with a fixed concentration (approximately 3× the previously determined EC50) of an agonist (usually 5-CT) at 5-HT2A or other appropriate agonists for other receptors. With both methods, cells were then grown in a humidified atmosphere with 5% ambient CO2 for five days. Media was then removed from the plates and marker gene activity was measured by the addition of the b-galactosidase substrate o-nitrophenyl b-D-galactopyranoside (ONPG, in PBS with 5% NP-40). The resulting colorimetric reaction was measured in a spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data were analyzed using the computer program XLFit (IDBSm). Efficacy is the percent maximal repression compared to repression by a control compound (ritanserin in the case of 5-HT2A). pIC50 is the negative of the log(IC50), where IC50 is the calculated concentration in molar that produces 50% maximal repression. The compounds as provided herein were assayed as described herein. Compounds of Formulas (I) and (II), demonstrated high inhibition of the 5-HT2A receptor activity as shown in the table below. This data below indicates that compounds as provide herein may be useful as pharmaceutical agents.
Measurement: Ki = 15.8 nM (pChEMBL 7.800000190734863)
Descriptors: MW 460.57, ALogP 5.08, HBA 4, HBD 0, PSA 42.01, QED 0.52
Compound (SMILES): O=c1[nH]c2nccc(Cl)c2c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc12
InChIKey: CLFYTABSRQFXOA-UHFFFAOYSA-N
Target: Aurora kinase A (SINGLE PROTEIN), Homo sapiens
UniProt: O14965
Assay: Kinase Inhibitory Activity: Assays are derived from other literature.
Measurement: IC50 = 550 nM (pChEMBL 6.260000228881836)
Descriptors: MW 462.94, ALogP 5.77, HBA 4, HBD 1, PSA 63.57, QED 0.34
Compound (SMILES): Cn1cc(NC(=O)c2csc3ncc(N4C[C@H]5CC[C@@H]4CN5)nc23)c(C#N)n1.O=C(O)C(F)(F)F
InChIKey: PSLGHQCYVKGTCB-NDXYWBNTSA-N
Target: Interleukin-1 receptor-associated kinase 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NWZ3
Assay: IRAK4 Kinase Assay: The kinase activity of IRAK4 is determined by its ability to catalyze the phosphorylation of a fluorescent polypeptide substrate. The extent of phosphorylation is measured using the IMAP technology (Molecular Devices) where the phosphorylated fluorescent substrate binds to the large M(III)-based nanoparticles which reduces the rotational speed of the substrate and thus increases its fluorescent polarization (FP).20 μL reaction mixture contains 10 mM TriHCl, pH 7.2, 0.5 nM GST tagged IRAK4 (SignalChem), 100 nM fluorescent peptide substrate (RP7030, Molecular Devices), 100 μM ATP, 1 mM DDT, 1 mM MgCl2, and 0.01% Tween 20. The reaction is initiated by the addition of ATP. After incubation for 30 minutes at 25° C., 60 μL of Progressive IMAP Reagent (Molecular Devices) is added to stop the reaction. Change in RP7030's FP is determined by a FP reader (Analyst HT, LJL BioSystems).
Measurement: IC50 = 37 nM (pChEMBL 7.429999828338623)
Descriptors: MW 394.46, ALogP 1.49, HBA 9, HBD 2, PSA 111.76, QED 0.69
Compound (SMILES): COC(=O)Nc1ccc(-c2ccc3cc(-c4nc5cc(C(=O)N6C[C@H]7CC[C@@H]6[C@@H]7N)cc(OC)c5n4C)n(CC4CC4)c3n2)c(F)c1F
InChIKey: QWUSGXQRLDGCBC-QMNWOKLKSA-N
Target: Protein-arginine deiminase type-4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UM07
Assay: Rapid-Fire Mass Spectrum (RFMS) Assay: Compounds were solubilized in 100% DMSO to achieve a 10 mM compound concentration. Compound stock solutions were stored at RT. A series of dilutions were prepared in DMSO and mixed 8 times with 20 μL mixing volume. Final top concentration of compound in the assay is 50 μM. Final assay conditions were as follows:Reaction volume: 26 μlAssay buffer: 25 mM hepes, pH 7.5, 5 mM NaCl, 1 mM DTT, 0.2 mg/ml BSA, 0.01% CHAPS, 50 μM Calcium, and 5 μM TPENFinal concentrations: 5 nM hPAD4 enzyme, 250 μM BAEE, and 0.5% DMSOTotal incubation time: 30 mins compound and enzyme preincubation at 37° C., 90 min enzyme/substrate reaction, 30 min reaction with phenyl glyoxal at 37° C.Stop solution: 40 μl 5% TCA in ACN
Measurement: IC50 = 137 nM (pChEMBL 6.860000133514404)
Descriptors: MW 655.71, ALogP 5.69, HBA 9, HBD 2, PSA 129.53, QED 0.23
Compound (SMILES): COc1cc(F)c(-c2cc(C(F)(F)F)c3c(N)ncnn23)cc1C(=O)N[C@@H]1CN(C(=O)CC(O)(C(F)(F)F)C(F)(F)F)C[C@@H]1F
InChIKey: YTPZGWVJDMJIKT-UONOGXRCSA-N
Target: Receptor-interacting serine/threonine-protein kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13546
Assay: RIPK1 HTRF Binding Assay: A solution was prepared containing 0.2 nM Anti GST-Tb (Cisbio, 61GSTTLB), 90.6 nM probe and 1 nM His-GST-TVMV-hRIPK1(1-324) in FRET Buffer (20 mM HEPES, 10 mM MgCl2, 0.015% Brij-35, 4 mM DTT, 0.05 mg/mL BSA). Using Formulatrix Tempest, the detection antibody/enzyme/probe solution (2 mL) was dispensed into wells of a 1536 plate (Black Low Binding Polystyrene 1536 Plate (Corning, 3724)) containing 10 nL of compounds of interest at appropriate concentration in DMSO. The plate was incubated at rt for 1 h. FRET was measured using the EnVision plate reader (Excitation: 340 nM, Emission: 520 nM/495 nM). Total signal (0% inhibition) was calculated from wells containing 10 nL DMSO only. Blank signal (100% inhibition) calculated from wells containing 10 nL of 15 nM staurosporine and internal controls.
Measurement: IC50 = 35000 nM (pChEMBL 4.460000038146973)
Descriptors: MW 664.43, ALogP 3.67, HBA 8, HBD 3, PSA 135.08, QED 0.34
Compound (SMILES): COc1cc(-c2cn(C)c(=O)c3cnccc23)cc(OC)c1CN1CC[C@H]1C(=O)NCCCCCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
InChIKey: GVWZEBMFVZAINC-CDRRMRQFSA-N
Target: Bromodomain-containing protein 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9H8M2
Assay: Bromodomain TR-FRET Competition Binding Assay: A mixture of biotinylated-ligand and SureLight Allophycocyanin-Streptavidin (APC-SA, PerkinElmer AD0201) in 50 mM HEPES (pH 7.4), 50 mM NaCl, 1 mM TCEP (pH 7), 0.01% (v/v) Tween-20, 0.01% (w/v) bovine serum albumin was added to a white 384-well PerkinElmer Proxiplate Plus plate. DMSO or 3-fold serially diluted compounds were then added to the Proxiplate followed by addition of Flag-BRD9. After a 10-minute incubation at room temperature, Eu-W1024 anti-FLAG (PerkinElmer, AD0273) was added. The final reaction miture that contained 3.75 nM biotinylated ligand, 3 nM Flag-BRD9, 7.5 nM SureLight Allophycocyanin-Streptavidin, and 0.2 nM Eu-W1024 anti-FLAG was incubated at room temperature for 90 minutes.
Measurement: IC50 > 10 nM (pChEMBL 8)
Descriptors: MW 791.91, ALogP 4.16, HBA 12, HBD 3, PSA 181.27, QED 0.1
Compound (SMILES): COCCOCCOCCOc1cc(Nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)cc(N)c4OC)c4ccccc34)n2)cc(OC)c1
InChIKey: XEIYTKCNVAGUBD-UHFFFAOYSA-N
Target: Glycogen synthase kinase-3 alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P49840
Assay: Enzyme Inhibition Assay: Method 2: This method follows the same steps as Method 1 above, but utilises a shorter period of mixing of the test compound (105 minutes instead of 2 hours) with the GSK3-α protein. In addition, the concentrations of test compound employed are either 10 ug/mL, 1 ug/mL, 0.1 ug/mL, or 0.01 ug/mL. Method 1: The inhibitory activities of compounds of the invention against the GSK 3α enzyme isoform (Invitrogen), are evaluated by determining the level of activation I phosphorylation of the target peptide. The GSK3-α protein (500 ng/mL, 2.5 uL) is mixed with the test compound (2.5 uL at either 4 ug/mL, 0.4 ug/mL, 0.04 ug/mL, or 0.004 ug/mL) for 2 hr at RT. The FRET peptide (8 uM, 2.5 uL), which is a phosphorylation target for GSK3α, and ATP (40 uM, 2.5 uL) are then added to the enzyme\compound mixture and the resulting mixture incubated for 1 hr. Development reagent (protease, 5 uL) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan Flash, ThermoFisher Scientific).
Measurement: IC50 = 1892 nM (pChEMBL 5.71999979019165)
Descriptors: MW 740.86, ALogP 7.77, HBA 12, HBD 4, PSA 169.57, QED 0.05
Compound (SMILES): CS(=O)(=O)c1cc(NC(=O)c2cnn(-c3cccc4ncccc34)c2C(F)(F)F)ccc1-n1nccn1
InChIKey: JLGFYCJJKJWKAA-UHFFFAOYSA-N
Target: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UDY8
Assay: In Vitro Assay: MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full-length MALT1 protein (Strep-MALT1(1-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 μM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM DTT, 1 mM EDTA, 0.05% BSA and 1.5% DMSO. Test compounds were spotted at 50 nL in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 μM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC). High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured.
Measurement: IC50 = 5754 nM (pChEMBL 5.239999771118164)
Descriptors: MW 527.49, ALogP 3.68, HBA 9, HBD 1, PSA 124.66, QED 0.37
Compound (SMILES): COc1cccnc1[C@H](CNC(=O)c1c(C)c(-c2ccccc2)nc2ccc(Br)cc12)CC(=O)O
InChIKey: YGUUYUPHOJCVCU-SFHVURJKSA-N
Target: Prostaglandin F2-alpha receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P43088
Assay: In Vitro Test of Inhibition of Human FP Receptor Activity: For the characterization of test substances in respect of FP antagonism, PGF2α-induced calcium flux in FP-expressing CHEM1 cells (Millipore, HTS093C) was used.3000 cells in 30 μl of full medium [DMEM F12, 10% FCS, 1.35 mM sodium pyruvate, 20 mM HEPES, 4 mM GlutaMAX, 2% sodium bicarbonate, 1% Pen/Strep, 1% 100× non-essential amino acids] are sown per well of a 384 multititre plate (from Greiner, TC plate, black with clear base) and incubated at 33° C., 5% CO2 for 24 hours. Prior to the measurement, the medium is replaced by 30 μl of Fluo-8 AM loading buffer [calcium-free Tyrode (130 mM NaCl, 5 mM KCl, 20 mM HEPES, 1 mM MgCl2, 4.8 mM NaHCO3, pH 7.4), 2 mM CaCl2, 6.3 mM Probenecid, 5 μM Fluo-8 AM, 0.0112% Pluronic®] and incubated at 37° C., 5% CO2 for 30 minutes. The test substance is prepared in DMSO in various concentrations as a dose-response curve (starting concentration 10 mM, dilution factor 3.16) and prediluted 1:50 with calcium-free Tyrode, 2 mM CaCl2, 0.002% SmartBlock (from CANDOR Bioscience GmbH). 10 μl of the prediluted substance solution are added to the Fluo-8-laden cells and incubated at 37° C., 5% CO2 for 10 minutes. The FP receptor is activated by adding 40 μl of 2 nM (final concentration) PGF2α in calcium-free Tyrode, 2 mM CaCl2, 0.002% SmartBlock, and the calcium flux is determined by measuring the fluorescence at ex. 470 nm/em. 525 nm in a fluorescence measuring instrument (FLIPR Tetra®, Molecular Devices) for 120 seconds.
Measurement: IC50 = 75 nM (pChEMBL 7.119999885559082)
Descriptors: MW 534.41, ALogP 5.36, HBA 5, HBD 2, PSA 101.41, QED 0.32
Compound (SMILES): CC(C)N1CCC(n2nc(-c3cc4cccc(O)c4[nH]3)c3c(N)ncnc32)CC1
InChIKey: XAWSEOWTVPLGSW-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Inhibition Assay: Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α, p110Î´/p85α from Upstate, and p110γ from Sigma) or expressed as previously described (Knight et al., 2004). IC50 values are measured using either a standard TLC assay for lipid kinase activity (described below) or a high-throughput membrane capture assay. Kinase reactions are performed by preparing a reaction mixture containing kinase, inhibitor (2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2), and freshly sonicated phosphatidylinositol (100 ug/ml). Reactions are initiated by the addition of ATP containing 10 uCi of γ-32P-ATP to a final concentration 10 or 100 uM and allowed to proceed for 5 minutes at room temperature. For TLC analysis, reactions are then terminated by the addition of 105 ul 1N HCl followed by 160 ul CHCl3:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged, and the organic phase is transferred to a new tube using a gel loading pipette tip precoated with CHCl3. This extract is spotted on TLC plates and developed for 3-4 hours in a 65:35 solution of n-propanol:1M acetic acid. The TLC plates are then dried, exposed to a phosphorimager screen (Storm, Amersham), and quantitated. For each compound, kinase activity is measured at 10-12 inhibitor concentrations representing two-fold dilutions from the highest concentration tested (typically, 200 uM).
Measurement: IC50 > 500 nM (pChEMBL 6.301000118255615)
Descriptors: MW 391.48, ALogP 3.31, HBA 7, HBD 3, PSA 108.88, QED 0.49
Compound (SMILES): CC(=O)Nc1nc(C[S+]([O-])c2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)cs1
InChIKey: UUOTYYPCIUJAJM-UHFFFAOYSA-N
Target: C-C chemokine receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P41597
Assay: Biological Assay: HEK-Gqi5 cells stably expressing CCR2 were cultured in (DMEM high glucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin. Appropriate positive control chemokines (MCP-1, MIP1A or RANTES) was used as the positive control agonist for screening compound-induced calcium activity assayed on the FLIPRTetra. The drug plates were prepared in 384-well microplates using the EP3 and the MuItiPROBE robotic liquid handling systems.
Measurement: IC50 = 2685 nM (pChEMBL 5.570000171661377)
Descriptors: MW 510.02, ALogP 4.61, HBA 7, HBD 2, PSA 124.36, QED 0.35