lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YAGUGWDMCPHBFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 7.1 nM (pChEMBL 8.149999618530273)
Descriptors: MW 324.39, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YBSXGRXZZZBXRI-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 38 nM (pChEMBL 7.420000076293945)
Descriptors: MW 310.36, ALogP 1.44, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCN(c1ncnc3[nH]ccc13)C2
InChIKey: PQJZDRGCMDQMMR-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Lck (SINGLE PROTEIN), Homo sapiens
UniProt: P06239
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human Lck using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 = 4700 nM (pChEMBL 5.329999923706055)
Descriptors: MW 332.31, ALogP 1.3, HBA 5, HBD 1, PSA 88.91, QED 0.9
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: VUHWQBJVFDDFAF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Lck (SINGLE PROTEIN), Homo sapiens
UniProt: P06239
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human Lck using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 = 2600 nM (pChEMBL 5.579999923706055)
Descriptors: MW 346.34, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.89
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCN(c1ncnc3[nH]ccc13)C2
InChIKey: LOWWYYZBZNSPDT-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 21 nM (pChEMBL 7.679999828338623)
Descriptors: MW 310.36, ALogP 1.3, HBA 5, HBD 1, PSA 88.91, QED 0.9
Compound (SMILES): N#CCC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: OTLJPDNWNUSUFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Lck (SINGLE PROTEIN), Homo sapiens
UniProt: P06239
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human Lck using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 = 6300 nM (pChEMBL 5.199999809265137)
Descriptors: MW 324.39, ALogP 1.83, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): CC(O)C(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: RMIDCDGTWBFPNH-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 150 nM (pChEMBL 6.820000171661377)
Descriptors: MW 329.4, ALogP 1.3, HBA 5, HBD 2, PSA 85.35, QED 0.87
Compound (SMILES): O=C(Nc1cc2ccc(OC3CCC[C@@H]3O)cc2cn1)C1CC1
InChIKey: FSLNTPWBGLDJGV-VYRBHSGPSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: In Vitro Enzyme Assay: Using the following procedure, varying concentration of compounds of the invention were assessed for their ability to inhibit c-Abl enzyme's phosphorylation of 5-FAM-EAIYAHPFAKKK-CONH2 (Caliper LifeSciences, cat #760346) peptide substrate in the presence of ATP at Km app. The phosphorylated product is detected using the Caliper mobility shift detection method where product and substrate are electrophoretically separated.
Measurement: Ki = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 312.37, ALogP 2.88, HBA 4, HBD 2, PSA 71.45, QED 0.91
Compound (SMILES): O=C(Nc1cc2ccc(OC3CCC[C@H]3O)cc2cn1)C1CC1
InChIKey: FSLNTPWBGLDJGV-AAFJCEBUSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: In Vitro Enzyme Assay: Using the following procedure, varying concentration of compounds of the invention were assessed for their ability to inhibit c-Abl enzyme's phosphorylation of 5-FAM-EAIYAHPFAKKK-CONH2 (Caliper LifeSciences, cat #760346) peptide substrate in the presence of ATP at Km app. The phosphorylated product is detected using the Caliper mobility shift detection method where product and substrate are electrophoretically separated.
Measurement: Ki = 0.2 nM (pChEMBL 9.699999809265137)
Descriptors: MW 312.37, ALogP 2.88, HBA 4, HBD 2, PSA 71.45, QED 0.91
Compound (SMILES): COc1cc2cnc(C(O)(c3cnn[nH]3)C(C)C)cc2cc1OC
InChIKey: FNQBQSDVRFAVIN-UHFFFAOYSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition Assay: In the design of clinically safe and effective metalloenzyme inhibitors, use of the most appropriate metal-binding group for the particular target and clinical indication is critical. If a weakly binding metal-binding group is utilized, potency may be suboptimal. On the other hand, if a very tightly binding metal-binding group is utilized, selectivity for the target enzyme versus related metalloenzymes may be suboptimal. The lack of optimal selectivity can be a cause for clinical toxicity due to unintended inhibition of these off-target metalloenzymes. One example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by the currently-available prostate anticancer agent ketoconazole. It is believed that this off-target inhibition is caused primarily by the indiscriminate binding of the currently utilized 1-imidazole to iron in the active site of CYP2C9, CYP2C19 and CYP3A4.
Measurement: IC50 = 33000 nM (pChEMBL 4.480000019073486)
Descriptors: MW 328.37, ALogP 2.26, HBA 6, HBD 2, PSA 93.15, QED 0.75
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C(=O)OC(C)(C)C)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: PDJFRJFTKGLDDM-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 1186 nM (pChEMBL 5.929999828338623)
Descriptors: MW 605.74, ALogP 6.38, HBA 8, HBD 2, PSA 112.58, QED 0.26
Compound (SMILES): CCN1CCN(C2CCc3cc(C(=O)Nc4ccc(C)c(Nc5nccc(-c6cccnc6)n5)c4)ccc32)CC1
InChIKey: JVGNHFZOVWJKER-UHFFFAOYSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 6.3 nM (pChEMBL 8.199999809265137)
Descriptors: MW 533.68, ALogP 5.47, HBA 7, HBD 2, PSA 86.28, QED 0.33
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C(C)C)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: PZINVJUNZRLUIM-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 23 nM (pChEMBL 7.639999866485596)
Descriptors: MW 547.71, ALogP 5.86, HBA 7, HBD 2, PSA 86.28, QED 0.3
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(CCO)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: JXVHQHBMOSSYBX-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 32 nM (pChEMBL 7.5)
Descriptors: MW 549.68, ALogP 4.44, HBA 8, HBD 3, PSA 106.51, QED 0.3
Compound (SMILES): CC(=O)N1CCN(C2CCc3cc(C(=O)Nc4ccc(C)c(Nc5nccc(-c6cccnc6)n5)c4)ccc32)CC1
InChIKey: AJIVJAKIEIICSU-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 529 nM (pChEMBL 6.28000020980835)
Descriptors: MW 547.66, ALogP 4.99, HBA 7, HBD 2, PSA 103.35, QED 0.35
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
InChIKey: IQOAIXAFDYRGNK-UHFFFAOYSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 266 nM (pChEMBL 6.579999923706055)
Descriptors: MW 520.64, ALogP 4.47, HBA 8, HBD 2, PSA 99.17, QED 0.38
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCC(N(C)C)C2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: PANUCCHSDROJBK-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 51 nM (pChEMBL 7.289999961853027)
Descriptors: MW 533.68, ALogP 5.47, HBA 7, HBD 2, PSA 86.28, QED 0.33
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CC[C@@H](N(C)C)C2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: PANUCCHSDROJBK-FIQOPJFZSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 70 nM (pChEMBL 7.159999847412109)
Descriptors: MW 533.68, ALogP 5.47, HBA 7, HBD 2, PSA 86.28, QED 0.33
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CC[C@@H]3N2CCN(C)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: YTHUQGIGAIZNIM-LJAQVGFWSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 2.2 nM (pChEMBL 8.65999984741211)
Descriptors: MW 519.65, ALogP 5.08, HBA 7, HBD 2, PSA 86.28, QED 0.37
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2ccncc2)n1
InChIKey: GMYQHOQOEQWZGN-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 526 nM (pChEMBL 6.28000020980835)
Descriptors: MW 519.65, ALogP 5.08, HBA 7, HBD 2, PSA 86.28, QED 0.37
Compound (SMILES): CCCNC(=S)c1ccc(-n2ccc3ccccc32)s1
InChIKey: OSMMLDCYRLJBKD-UHFFFAOYSA-N
Target: Dihydroorotate dehydrogenase (quinone), mitochondrial (SINGLE PROTEIN), Homo sapiens
UniProt: Q02127
Assay: Enzymatic Assays: Type 2 DHODH activity was monitored with either the direct assay measuring the formation of orotate or via a chromogen reduction assay using DCIP. Although the extinction coefficient and absorption wavelength are preferable for the chromogen reduction assay, the inorganic electron acceptor DCIP can be utilized by DHODH as the final electron acceptor in lieu of CoQn when the endogenous substrate is at a low concentration. As such, the direct assay was used to measure the binding affinity of pfDHODH to CoQD and L-DHO. The enzymatic reaction was performed by varying the L-DHO concentration (1-400 μM) or CoQD concentration (1-200 μM) while keeping the other substrate constant and in excess. Inhibition of DHODH by small molecules was evaluated using the chromogen based assay with a final substrate concentration of 200 μM L-DHO, 18 μM CoQD, and 100 μM DCIP, unless otherwise noted.
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 300.45, ALogP 4.37, HBA 3, HBD 1, PSA 16.96, QED 0.72
Compound (SMILES): CCCNC(=O)c1ccc(-n2c(C)nc3ccccc32)s1
InChIKey: KBBUJPFPTIFZBX-UHFFFAOYSA-N
Target: Dihydroorotate dehydrogenase (SINGLE PROTEIN), Plasmodium falciparum
UniProt: Q54A96
Assay: Enzymatic Assays: Type 2 DHODH activity was monitored with either the direct assay measuring the formation of orotate or via a chromogen reduction assay using DCIP. Although the extinction coefficient and absorption wavelength are preferable for the chromogen reduction assay, the inorganic electron acceptor DCIP can be utilized by DHODH as the final electron acceptor in lieu of CoQn when the endogenous substrate is at a low concentration. As such, the direct assay was used to measure the binding affinity of pfDHODH to CoQD and L-DHO. The enzymatic reaction was performed by varying the L-DHO concentration (1-400 μM) or CoQD concentration (1-200 μM) while keeping the other substrate constant and in excess. Inhibition of DHODH by small molecules was evaluated using the chromogen based assay with a final substrate concentration of 200 μM L-DHO, 18 μM CoQD, and 100 μM DCIP, unless otherwise noted.
Measurement: IC50 = 172 nM (pChEMBL 6.760000228881836)
Descriptors: MW 299.4, ALogP 3.54, HBA 4, HBD 1, PSA 46.92, QED 0.8
Compound (SMILES): O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(/C=C/c4ccccn4)ccn23)c1
InChIKey: DMLTXHUJLWPBCX-BQYQJAHWSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: In Vitro Kinase Inhibition Assay: VEGFR2 (from Upstate), prepared at 2x final concentration, was incubated with test compounds, biotinylated Flt3 substrate (biotin-VASSDNEYFYVDF) (Cell Signalling Technology Inc.) and ATP in the appropriate assay buffer (Table 1). The reaction was allowed to proceed for 1 hour at room temperature on a plate shaker at 700 rpm before being stopped with 35 mM EDTA, pH 8 (VEGFR2). 5x detection mix (50 mM HEPES, pH 7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (PY20), 187.5 nM SA-XL665) was then added to each well and the plate sealed and incubated at room temperature for one hour on a plate shaker at 700 rpm. The plate was then read on a Packard Fusion plate reader or a BMG Pherastar both in TRF mode. Kinase Assay buffers were: 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.01% TritonX-100, 0.1 mM Sodium orthovanadate.
Measurement: IC50 = 95.4 nM (pChEMBL 7.019999980926514)
Descriptors: MW 437.43, ALogP 5.25, HBA 4, HBD 2, PSA 71.32, QED 0.45
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YAGUGWDMCPHBFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 14 nM (pChEMBL 7.849999904632568)
Descriptors: MW 324.39, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YBSXGRXZZZBXRI-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK2 kinase domain (aa808-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 2.2 nM (pChEMBL 8.65999984741211)
Descriptors: MW 310.36, ALogP 1.44, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCN(c1ncnc3[nH]ccc13)C2
InChIKey: PQJZDRGCMDQMMR-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 5.1 nM (pChEMBL 8.289999961853027)
Descriptors: MW 332.31, ALogP 1.3, HBA 5, HBD 1, PSA 88.91, QED 0.9
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: VUHWQBJVFDDFAF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 346.34, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.89
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCN(c1ncnc3[nH]ccc13)C2
InChIKey: LOWWYYZBZNSPDT-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK2 kinase domain (aa808-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 2.1 nM (pChEMBL 8.680000305175781)
Descriptors: MW 310.36, ALogP 1.3, HBA 5, HBD 1, PSA 88.91, QED 0.9
Compound (SMILES): N#CCC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: OTLJPDNWNUSUFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 5.8 nM (pChEMBL 8.239999771118164)
Descriptors: MW 324.39, ALogP 1.83, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): O=C(Nc1cc2ccc(OC3CCC[C@H]3O)cc2cn1)C1CC1
InChIKey: FSLNTPWBGLDJGV-AAFJCEBUSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: In Vitro Enzyme Assay: Using the following procedure, varying concentration of compounds of the invention were assessed for their ability to inhibit c-Abl enzyme's phosphorylation of 5-FAM-EAIYAHPFAKKK-CONH2 (Caliper LifeSciences, cat #760346) peptide substrate in the presence of ATP at Km app. The phosphorylated product is detected using the Caliper mobility shift detection method where product and substrate are electrophoretically separated.
Measurement: Ki = 13 nM (pChEMBL 7.889999866485596)
Descriptors: MW 312.37, ALogP 2.88, HBA 4, HBD 2, PSA 71.45, QED 0.91
Compound (SMILES): COc1cc2cnc(C(O)(c3cnn[nH]3)C(C)C)cc2cc1OC
InChIKey: FNQBQSDVRFAVIN-UHFFFAOYSA-N
Target: Steroid 17-alpha-hydroxylase/17,20 lyase (SINGLE PROTEIN), Homo sapiens
UniProt: P05093
Assay: Inhibition Assay: In the design of clinically safe and effective metalloenzyme inhibitors, use of the most appropriate metal-binding group for the particular target and clinical indication is critical. If a weakly binding metal-binding group is utilized, potency may be suboptimal. On the other hand, if a very tightly binding metal-binding group is utilized, selectivity for the target enzyme versus related metalloenzymes may be suboptimal. The lack of optimal selectivity can be a cause for clinical toxicity due to unintended inhibition of these off-target metalloenzymes. One example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by the currently-available prostate anticancer agent ketoconazole. It is believed that this off-target inhibition is caused primarily by the indiscriminate binding of the currently utilized 1-imidazole to iron in the active site of CYP2C9, CYP2C19 and CYP3A4.
Measurement: IC50 = 960 nM (pChEMBL 6.019999980926514)
Descriptors: MW 328.37, ALogP 2.26, HBA 6, HBD 2, PSA 93.15, QED 0.75
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: YTHUQGIGAIZNIM-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 2251 nM (pChEMBL 5.650000095367432)
Descriptors: MW 519.65, ALogP 5.08, HBA 7, HBD 2, PSA 86.28, QED 0.37
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCNCC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: SZPKERXOPUWUPW-UHFFFAOYSA-N
Target: Platelet-derived growth factor receptor beta (SINGLE PROTEIN), Homo sapiens
UniProt: P09619
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 12 nM (pChEMBL 7.920000076293945)
Descriptors: MW 505.63, ALogP 4.74, HBA 7, HBD 3, PSA 95.07, QED 0.35
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
InChIKey: IQOAIXAFDYRGNK-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 32 nM (pChEMBL 7.5)
Descriptors: MW 520.64, ALogP 4.47, HBA 8, HBD 2, PSA 99.17, QED 0.38
Compound (SMILES): O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(/C=C/c4ccccn4)ccn23)c1
InChIKey: DMLTXHUJLWPBCX-BQYQJAHWSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: In Vitro Kinase Inhibition Assay: VEGFR2 (from Upstate), prepared at 2x final concentration, was incubated with test compounds, biotinylated Flt3 substrate (biotin-VASSDNEYFYVDF) (Cell Signalling Technology Inc.) and ATP in the appropriate assay buffer (Table 1). The reaction was allowed to proceed for 1 hour at room temperature on a plate shaker at 700 rpm before being stopped with 35 mM EDTA, pH 8 (VEGFR2). 5x detection mix (50 mM HEPES, pH 7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (PY20), 187.5 nM SA-XL665) was then added to each well and the plate sealed and incubated at room temperature for one hour on a plate shaker at 700 rpm. The plate was then read on a Packard Fusion plate reader or a BMG Pherastar both in TRF mode. Kinase Assay buffers were: 50 mM HEPES pH 7.5, 6 mM MnCl2, 1 mM DTT, 0.01% TritonX-100, 0.1 mM Sodium orthovanadate.
Measurement: IC50 = 200 nM (pChEMBL 6.699999809265137)
Descriptors: MW 437.43, ALogP 5.25, HBA 4, HBD 2, PSA 71.32, QED 0.45
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YAGUGWDMCPHBFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK2 kinase domain (aa808-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 1 nM (pChEMBL 9)
Descriptors: MW 324.39, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YBSXGRXZZZBXRI-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition of human JAK3 (780 to end residues) expressed in baculovirus infected Sf9 cells using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 310.36, ALogP 1.44, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCN(c1ncnc3[nH]ccc13)C2
InChIKey: PQJZDRGCMDQMMR-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 12 nM (pChEMBL 7.920000076293945)
Descriptors: MW 332.31, ALogP 1.3, HBA 5, HBD 1, PSA 88.91, QED 0.9
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: VUHWQBJVFDDFAF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 88 nM (pChEMBL 7.059999942779541)
Descriptors: MW 346.34, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.89
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCN(c1ncnc3[nH]ccc13)C2
InChIKey: LOWWYYZBZNSPDT-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Lck (SINGLE PROTEIN), Homo sapiens
UniProt: P06239
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human Lck using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 310.36, ALogP 1.3, HBA 5, HBD 1, PSA 88.91, QED 0.9
Compound (SMILES): N#CCC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: OTLJPDNWNUSUFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 14 nM (pChEMBL 7.849999904632568)
Descriptors: MW 324.39, ALogP 1.83, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
InChIKey: IQOAIXAFDYRGNK-UHFFFAOYSA-N
Target: Platelet-derived growth factor receptor beta (SINGLE PROTEIN), Homo sapiens
UniProt: P09619
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 13 nM (pChEMBL 7.889999866485596)
Descriptors: MW 520.64, ALogP 4.47, HBA 8, HBD 2, PSA 99.17, QED 0.38
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YAGUGWDMCPHBFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK2 kinase domain (aa808-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 1.7 nM (pChEMBL 8.770000457763672)
Descriptors: MW 324.39, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YBSXGRXZZZBXRI-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Lck (SINGLE PROTEIN), Homo sapiens
UniProt: P06239
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human Lck using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 = 3700 nM (pChEMBL 5.429999828338623)
Descriptors: MW 310.36, ALogP 1.44, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCN(c1ncnc3[nH]ccc13)C2
InChIKey: PQJZDRGCMDQMMR-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK2 kinase domain (aa808-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 1.7 nM (pChEMBL 8.770000457763672)
Descriptors: MW 332.31, ALogP 1.3, HBA 5, HBD 1, PSA 88.91, QED 0.9
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: VUHWQBJVFDDFAF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK3 kinase domain (aa781-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 3.3 nM (pChEMBL 8.479999542236328)
Descriptors: MW 346.34, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.89
Compound (SMILES): N#CCC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: OTLJPDNWNUSUFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK2 kinase domain (aa808-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 4.7 nM (pChEMBL 8.329999923706055)
Descriptors: MW 324.39, ALogP 1.83, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: YTHUQGIGAIZNIM-UHFFFAOYSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 5.8 nM (pChEMBL 8.239999771118164)
Descriptors: MW 519.65, ALogP 5.08, HBA 7, HBD 2, PSA 86.28, QED 0.37
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
InChIKey: IQOAIXAFDYRGNK-UHFFFAOYSA-N
Target: Platelet-derived growth factor receptor beta (SINGLE PROTEIN), Homo sapiens
UniProt: P09619
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 65 nM (pChEMBL 7.190000057220459)
Descriptors: MW 520.64, ALogP 4.47, HBA 8, HBD 2, PSA 99.17, QED 0.38
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YAGUGWDMCPHBFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition of human JAK3 (780 to end residues) expressed in baculovirus infected Sf9 cells using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 324.39, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): N#CCC(=O)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: VUHWQBJVFDDFAF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition Assay: In the kinase reactions, fused proteins (6His tag-fused hJAK2 kinase domain (aa808-end)) which were coexpressed in Sf21 cells and purified by Ni2+/NTA agarose were used.
Measurement: IC50 = 1.9 nM (pChEMBL 8.720000267028809)
Descriptors: MW 346.34, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.89
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: YTHUQGIGAIZNIM-UHFFFAOYSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 256 nM (pChEMBL 6.590000152587891)
Descriptors: MW 519.65, ALogP 5.08, HBA 7, HBD 2, PSA 86.28, QED 0.37
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
InChIKey: IQOAIXAFDYRGNK-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 2260 nM (pChEMBL 5.650000095367432)
Descriptors: MW 520.64, ALogP 4.47, HBA 8, HBD 2, PSA 99.17, QED 0.38
Compound (SMILES): CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
InChIKey: YAGUGWDMCPHBFF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Lck (SINGLE PROTEIN), Homo sapiens
UniProt: P06239
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human Lck using TK-substrate-biotin as substrate incubated for 60 mins in presence of ATP by fluorescence method
Measurement: IC50 = 1500 nM (pChEMBL 5.820000171661377)
Descriptors: MW 324.39, ALogP 1.69, HBA 5, HBD 1, PSA 88.91, QED 0.91
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cccnc2)n1
InChIKey: YTHUQGIGAIZNIM-UHFFFAOYSA-N
Target: Platelet-derived growth factor receptor beta (SINGLE PROTEIN), Homo sapiens
UniProt: P09619
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 17 nM (pChEMBL 7.769999980926514)
Descriptors: MW 519.65, ALogP 5.08, HBA 7, HBD 2, PSA 86.28, QED 0.37
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
InChIKey: IQOAIXAFDYRGNK-UHFFFAOYSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 2.4 nM (pChEMBL 8.619999885559082)
Descriptors: MW 520.64, ALogP 4.47, HBA 8, HBD 2, PSA 99.17, QED 0.38
Compound (SMILES): Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
InChIKey: IQOAIXAFDYRGNK-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Enzyme Assay: The activity of the compounds of this invention on Abl, c-Kit and PDGFR kinases was tested by Mobility Shift Assay (MSA). Kinase buffer: 62.5 mM HEPES, pH 7.5; 0.001875% Brij-35; 12.5 mM MgCl2; 2.5 mM DTT. Stop buffer: 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% coating agent 3; 50 mM EDTA. Preparation of kinase solution: Kinase solution was obtained by dissolving kinases in the kinase buffer mentioned above. With regard to c-Kit kinase, the pre-activation treatments should be carried out as follows. 700 nM c-Kit, 2 mM ATP, 4 mM DTT and 10 mM MgCl2 were dissolved in kinase buffer. After being incubated at 28° C. for 15 minutes, the solution was added to the kinase buffer.
Measurement: IC50 = 15 nM (pChEMBL 7.820000171661377)
Descriptors: MW 520.64, ALogP 4.47, HBA 8, HBD 2, PSA 99.17, QED 0.38
Compound (SMILES): Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(F)c(C(F)(F)F)c4)cs3)coc2n(C)c1=O
InChIKey: HXYKQFXGQHGPRG-UHFFFAOYSA-N
Target: Transient receptor potential cation channel subfamily V member 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q8NER1
Assay: Radiometric Calcium Assay: The inhibition of TRPA1 receptor activation was measured as inhibition of allylisothiocyanate (AITC) induced cellular uptake of radioactive calcium. Test compounds were dissolved in DMSO to prepare 10 mM stock solution and then diluted using plain medium with 0.1% BSA and 1.8 mM CaCl2 to get desired concentration. Final concentration of DMSO in the reaction was 0.5% (v/v). Human TRPA1 expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 ug/ml of G-418. Cells were seeded 24 h prior to the assay in 96 well plates so as to get 50,000 cells per well on the day of experiment. Cells were treated with test compounds for 10 min followed by addition of AITC at a final concentration of 30 micromolar and 5 uCi/ml 45Ca+2 for 3 min at 25° C. Cells were washed and lysed using buffer containing 1% Triton X-100, 0.1% deoxycholate and 0.1% SDS. Radioactivity in the lysate was measured in Packard Top count.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 482.42, ALogP 3.29, HBA 8, HBD 1, PSA 99.13, QED 0.45
Compound (SMILES): O=C(CC1([C@H]2CO[C@H]3CCC[C@H]3N2S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCC(N2CCCCC2)CC1
InChIKey: YFCCLDWKIOBOCQ-UODIDJSMSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of recombinant human CYP3A4 expressed in baculovirus infected insect cells preincubated for 30 mins using fluorescent substrate
Measurement: IC50 = 8000 nM (pChEMBL 5.099999904632568)
Descriptors: MW 550.17, ALogP 4.3, HBA 5, HBD 0, PSA 70.16, QED 0.53
Compound (SMILES): COCC(O)CN(c1cc(OC)cc(OC)c1)c1ccc2ncc(-c3cnn(C)c3)nc2c1
InChIKey: IVVNCQGZOKJKEC-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P22607
Assay: Inhibition of FGFR3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in presence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 449.51, ALogP 3.19, HBA 9, HBD 1, PSA 94.76, QED 0.42
Compound (SMILES): COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2-c2cc(Cl)cc(NS(C)(=O)=O)c2)n1
InChIKey: AZFXVYSHIJAZOU-AWEZNQCLSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Inhibition of B-Raf V600E mutant in human A375 cells harboring B-Raf V600E mutant assessed as reduction in cell proliferation incubated for 2 days by Bright-Glo luminescence assay
Measurement: IC50 = 18 nM (pChEMBL 7.75)
Descriptors: MW 522.03, ALogP 3.77, HBA 9, HBD 3, PSA 140.13, QED 0.39
Compound (SMILES): COc1cc(OC)cc(N(c2ccc3ncc(-c4cnn(C)c4)nc3c2)C(C)CNC(C)C)c1
InChIKey: DVBMTJCMGPJACG-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P22607
Assay: Inhibition of FGFR3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in presence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 460.58, ALogP 4.57, HBA 8, HBD 1, PSA 77.33, QED 0.39
Compound (SMILES): Cc1cccc(N2C(=O)c3ccccc3C2(O)c2ccc3nc(Nc4ncccn4)[nH]c3c2)c1
InChIKey: NDPRSQKMCOPISW-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Inhibition of B-Raf (unknown origin) pre-incubated for 30 mins by luciferase-luciferin-coupled chemiluminescence assay
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 448.49, ALogP 4.26, HBA 6, HBD 3, PSA 107.03, QED 0.38