lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C[C@@H](C#N)OC5=O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: UJVLGBLCHOLBIE-OVRAVGDNSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 550 nM (pChEMBL 6.260000228881836)
Descriptors: MW 498.43, ALogP 0.71, HBA 10, HBD 2, PSA 167.1, QED 0.53
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C(=O)OC[C@@H]5[C@@H](C)O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: ZLLGWBWCYXJDQS-BIMRVWLLSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 530 nM (pChEMBL 6.28000020980835)
Descriptors: MW 517.47, ALogP 0.56, HBA 10, HBD 3, PSA 163.54, QED 0.48
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C(=O)O[C@H](C)[C@@H]5CF)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: FMOMXEHQGBMACL-HEGZVTDKSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 440 nM (pChEMBL 6.360000133514404)
Descriptors: MW 519.46, ALogP 1.54, HBA 9, HBD 2, PSA 143.31, QED 0.56
Compound (SMILES): COC[C@@H]1[C@@H](C)OC(=O)N1c1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
InChIKey: VCOQBXCFOJNURZ-LHBVMDHGSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 170 nM (pChEMBL 6.769999980926514)
Descriptors: MW 531.5, ALogP 1.22, HBA 10, HBD 2, PSA 152.54, QED 0.55
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C(=O)OC[C@@H]5C5CCOCC5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: OJVBQPLPLOUYNK-LLHLMSRXSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 530 nM (pChEMBL 6.28000020980835)
Descriptors: MW 557.54, ALogP 1.61, HBA 10, HBD 2, PSA 152.54, QED 0.52
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C(=O)OC[C@H]5CN=[N+]=[N-])noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: VDYFDGAKQSHMCQ-OVRAVGDNSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 150 nM (pChEMBL 6.820000171661377)
Descriptors: MW 528.46, ALogP 1.49, HBA 10, HBD 2, PSA 192.07, QED 0.26
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C[C@H](c6ccccn6)OC5=O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: HRDUNBHXUGTYRL-LLHLMSRXSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 380 nM (pChEMBL 6.420000076293945)
Descriptors: MW 550.5, ALogP 1.95, HBA 10, HBD 2, PSA 156.2, QED 0.45
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C(=O)OC[C@H]5c5ccccn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: ISYLVRUSGYTPNY-QMERHICCSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 150 nM (pChEMBL 6.820000171661377)
Descriptors: MW 550.5, ALogP 1.95, HBA 10, HBD 2, PSA 156.2, QED 0.45
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C(=O)OC[C@H]5c5ccncc5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
InChIKey: WKLLYHUVQLJJCU-QMERHICCSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 760 nM (pChEMBL 6.119999885559082)
Descriptors: MW 550.5, ALogP 1.95, HBA 10, HBD 2, PSA 156.2, QED 0.45
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C(=O)OC[C@H]5c5ncccn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)C2[C@H](C)O1
InChIKey: XNHIBFIYRMMRCU-KISLSHQNSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 340 nM (pChEMBL 6.46999979019165)
Descriptors: MW 551.49, ALogP 1.35, HBA 11, HBD 2, PSA 169.09, QED 0.44
Compound (SMILES): C[C@@H]1CN2c3c(cc4c(N5C[C@H](C#N)OC5=O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)C2[C@H](C)O1
InChIKey: UJVLGBLCHOLBIE-GLTJXIQLSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 = 710 nM (pChEMBL 6.150000095367432)
Descriptors: MW 498.43, ALogP 0.71, HBA 10, HBD 2, PSA 167.1, QED 0.53
Compound (SMILES): COC[C@H]1[C@@H](C)OC(=O)N1c1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)C1[C@H](C)O[C@H](C)CN31
InChIKey: VCOQBXCFOJNURZ-PPKYZZFTSA-N
Target: DNA gyrase subunit A (SINGLE PROTEIN), Escherichia coli K-12
UniProt: P0AES4
Assay: Fluorescence Polarisation Assay: In a black, 384-well polystyrene assay plate, 30 microliters/well of 5 nM Escherichia coli DNA gyrase A/B tetramer and 130 micrograms/mL of topological^ relaxed plasmid containing the triplex-forming sequence TTCTTCTTCTTCTTCTTCTTCTTCTTC (SEQ ID NO: 1) in an assay buffer consisting of 35 mM Tris-HCI (pH 7.5), 24 mM KCI, 4 mM MgCI2, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v) glycerol, 200 nM bovine serum albumin, 0.8%dimethylsulfoxide, and 0.3 mM ATP were incubated at ambient temperature for (typically 30 minutes) in the absence or presence of 5 -10 different concentrations of test compound. The supercoiling reactions were quenched by the addition of 10 microliters/well of 40 nM oligodeoxynucleotide probe in 3X triplex-forming buffer consisting of 150 mM NaCI, and 150 mM sodium acetate at pH 3.5. The oligodeoxynucleotide probe was 5'-BODIPY-FL-labeled TTCTTCTTC (SEQ ID NO:2). After 60 minutes, the fluorescence anisotropy of the BODIPY- FL was measured in a Tecan Ultra plate.
Measurement: IC50 > 2100 nM (pChEMBL 5.677999973297119)
Descriptors: MW 531.5, ALogP 1.22, HBA 10, HBD 2, PSA 152.54, QED 0.55
Compound (SMILES): CCOC(=O)c1c(-c2ccc(NC(C)=O)cc2)csc1N
InChIKey: RKGOKRGBGUQYQN-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 6000 nM (pChEMBL 5.21999979019165)
Descriptors: MW 304.37, ALogP 3.13, HBA 5, HBD 2, PSA 81.42, QED 0.85
Compound (SMILES): COc1cccc(COC(=O)c2c(-c3ccc(C(N)=O)cc3)csc2N)c1
InChIKey: PZLGAGDROBQFAL-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 6000 nM (pChEMBL 5.21999979019165)
Descriptors: MW 382.44, ALogP 3.46, HBA 6, HBD 2, PSA 104.64, QED 0.64
Compound (SMILES): NC(=O)c1ccc(-c2csc(N)c2C(=O)OCc2ccccc2)cc1
InChIKey: RSQKRFLIPSAOAW-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 11000 nM (pChEMBL 4.960000038146973)
Descriptors: MW 352.42, ALogP 3.45, HBA 5, HBD 2, PSA 95.41, QED 0.69
Compound (SMILES): CC(C)OC(=O)c1c(-c2ccc3c(c2)OCO3)csc1N
InChIKey: JFYGZNMEZXPYFF-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 21000 nM (pChEMBL 4.679999828338623)
Descriptors: MW 305.36, ALogP 3.29, HBA 6, HBD 1, PSA 70.78, QED 0.88
Compound (SMILES): COc1ccc(-c2csc(N)c2C(=O)N2CCOCC2)cc1OC
InChIKey: GMQDXCYJGRIXJX-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 4000 nM (pChEMBL 5.400000095367432)
Descriptors: MW 348.42, ALogP 2.49, HBA 6, HBD 1, PSA 74.02, QED 0.92
Compound (SMILES): CC(C)NC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N
InChIKey: PZJLIRKPEYSJAF-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 5000 nM (pChEMBL 5.300000190734863)
Descriptors: MW 329.25, ALogP 4.44, HBA 3, HBD 2, PSA 55.12, QED 0.87
Compound (SMILES): Nc1scc(-c2ccc(Cl)c(Cl)c2)c1C(=O)N1CCOCC1
InChIKey: IPBYVADTPAHBJS-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 3000 nM (pChEMBL 5.519999980926514)
Descriptors: MW 357.26, ALogP 3.78, HBA 4, HBD 1, PSA 55.56, QED 0.89
Compound (SMILES): CCNC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N
InChIKey: CRXGEGYGRHUOJY-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Luminescence-Based Kinase Assay: IC50 values were determined using an in vitro luminescence-based kinase assay against aPKCζ to elucidate a pharmacophore. The IC50 values determined for isopropyl 2-amino-4-(3,4-dimethoxyphenyl)thiophene-3-carboxylate (also referred to as PKCl-diMeO, PKCζl-diMeO, or PKCzl3), and compounds described herein and illustrated in FIGS. 1, 3, and 7 are described in Table 1. The IC50 values were determined using an ADP Quest assay with 500 ng/ml aPKCζ, 10 μM CREBtide, and 10 μM ATP. In PKCζ kinase activity assays using 30 μM of candidate compound, PKCl-diMeO and the compounds illustrated in FIG. 7 resulted in a 55-100% inhibition in kinase activity.
Measurement: IC50 = 5000 nM (pChEMBL 5.300000190734863)
Descriptors: MW 315.23, ALogP 4.05, HBA 3, HBD 2, PSA 55.12, QED 0.9
Compound (SMILES): CCOC(=O)c1c(-c2ccc(F)cc2)csc1N
InChIKey: CJMZLCRLBNZJQR-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Kinase-Glo End-Point Assay: The IC50 values for PKCl-diMeO and compounds described herein and illustrated in FIG. 6 are described in Table 2. The IC50 values were determined using a Kinase-Glo end-point assay with 125 ng/ml aPKCζ, 25 μM CREBtide, and 0.1 μM ATP.
Measurement: IC50 = 26000 nM (pChEMBL 4.579999923706055)
Descriptors: MW 265.31, ALogP 3.31, HBA 4, HBD 1, PSA 52.32, QED 0.87
Compound (SMILES): CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)csc1N
InChIKey: PZUSHWNNJRFJFD-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Kinase-Glo End-Point Assay: The IC50 values for PKCl-diMeO and compounds described herein and illustrated in FIG. 6 are described in Table 2. The IC50 values were determined using a Kinase-Glo end-point assay with 125 ng/ml aPKCζ, 25 μM CREBtide, and 0.1 μM ATP.
Measurement: IC50 = 41000 nM (pChEMBL 4.389999866485596)
Descriptors: MW 292.32, ALogP 3.08, HBA 6, HBD 1, PSA 95.46, QED 0.53
Compound (SMILES): COC(=O)c1c(-c2ccc(Br)cc2)csc1N
InChIKey: FTCYGPXJXBDSIU-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Kinase-Glo End-Point Assay: The IC50 values for PKCl-diMeO and compounds described herein and illustrated in FIG. 6 are described in Table 2. The IC50 values were determined using a Kinase-Glo end-point assay with 125 ng/ml aPKCζ, 25 μM CREBtide, and 0.1 μM ATP.
Measurement: IC50 = 28000 nM (pChEMBL 4.550000190734863)
Descriptors: MW 312.19, ALogP 3.55, HBA 4, HBD 1, PSA 52.32, QED 0.86
Compound (SMILES): CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N
InChIKey: YHJWJJKFFNCDCK-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Kinase-Glo End-Point Assay: The IC50 values for PKCl-diMeO and compounds described herein and illustrated in FIG. 6 are described in Table 2. The IC50 values were determined using a Kinase-Glo end-point assay with 125 ng/ml aPKCζ, 25 μM CREBtide, and 0.1 μM ATP.
Measurement: IC50 = 39000 nM (pChEMBL 4.409999847412109)
Descriptors: MW 281.76, ALogP 3.83, HBA 4, HBD 1, PSA 52.32, QED 0.87
Compound (SMILES): CCOC(=O)c1c(NC(C)=O)sc(C(C)=O)c1-c1ccc(Cl)cc1
InChIKey: FOVNOIYDJMJWRZ-UHFFFAOYSA-N
Target: Protein kinase C zeta type (SINGLE PROTEIN), Homo sapiens
UniProt: Q05513
Assay: Kinase-Glo End-Point Assay: The IC50 values for PKCl-diMeO and compounds described herein and illustrated in FIG. 6 are described in Table 2. The IC50 values were determined using a Kinase-Glo end-point assay with 125 ng/ml aPKCζ, 25 μM CREBtide, and 0.1 μM ATP.
Measurement: IC50 = 71000 nM (pChEMBL 4.150000095367432)
Descriptors: MW 365.84, ALogP 4.41, HBA 5, HBD 1, PSA 72.47, QED 0.63
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncc(OC)c3)c3nc(N4CCN(C)CC4)ccc32)c1F
InChIKey: WEPJHIJXYRZXRB-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 297 nM (pChEMBL 6.53000020980835)
Descriptors: MW 556.64, ALogP 4.28, HBA 8, HBD 1, PSA 92.59, QED 0.35
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncc(OC)c3)c3nc(N4CCN(CCOC)CC4)ccc32)c1F
InChIKey: XYNLRUGZVMUSSG-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 125 nM (pChEMBL 6.900000095367432)
Descriptors: MW 600.69, ALogP 4.29, HBA 9, HBD 1, PSA 101.82, QED 0.27
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncc(OC)c3)c3nc(N(C)C4CCN(C)CC4)cnc32)c1F
InChIKey: IIABPOATXMCFIP-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 16 nM (pChEMBL 7.800000190734863)
Descriptors: MW 585.68, ALogP 4.45, HBA 9, HBD 1, PSA 105.48, QED 0.31
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncc(OC)c3)c3nc(N4CCN(C)CC4)ncc32)c1F
InChIKey: VRBVJJNNGVPJKG-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 1613 nM (pChEMBL 5.789999961853027)
Descriptors: MW 557.63, ALogP 3.67, HBA 9, HBD 1, PSA 105.48, QED 0.35
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncc(OC)c3)c3nc(N(C)C4CCN(C)CC4)ncc32)c1F
InChIKey: OGYLFLLUTHXQGA-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 7 nM (pChEMBL 8.149999618530273)
Descriptors: MW 585.68, ALogP 4.45, HBA 9, HBD 1, PSA 105.48, QED 0.31
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncnc3)c3nc(N(C)C4CCN(C)CC4)ncc32)c1F
InChIKey: SIELDIVHIBIXDN-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 556.64, ALogP 3.84, HBA 9, HBD 1, PSA 109.14, QED 0.35
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncnc3)c3nc(N(C)C4CCN(CC)CC4)ncc32)c1F
InChIKey: DZKPRXZJIJDQLW-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 16 nM (pChEMBL 7.800000190734863)
Descriptors: MW 570.67, ALogP 4.23, HBA 9, HBD 1, PSA 109.14, QED 0.32
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncnc3)c3nc(N(C)C4CCN(C5CC5)CC4)ncc32)c1F
InChIKey: ORMCSYVTCMPLGE-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 29 nM (pChEMBL 7.539999961853027)
Descriptors: MW 582.68, ALogP 4.37, HBA 9, HBD 1, PSA 109.14, QED 0.31
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncnc3)c3nc(N(C)C4CCN(CCOC)CC4)ncc32)c1F
InChIKey: RPTJDORVFYKUBD-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 42 nM (pChEMBL 7.380000114440918)
Descriptors: MW 600.7, ALogP 3.85, HBA 10, HBD 1, PSA 118.37, QED 0.27
Compound (SMILES): CCCS(=O)(=O)Nc1ccc(F)c(-n2cc(-c3cncnc3)c3nc(N(C)C4CCNCC4)ncc32)c1F
InChIKey: IGWKRBJOHCFQRT-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: Kinase Assay: In a dilution series 10 uL/well of test substance solution are placed in a multiwell plate. The dilution series is selected so that generally a range of concentrations of 2 uM to 0.119 nM or 0.017 nM is covered. If necessary the initial concentration of 2 uM is changed to 50 uM, 10 uM, 0.4 uM or 0.2857 uM and further dilution is carried out accordingly. The final concentration of DMSO is 5%. 10 uL/well of the B-Raf (V600E)-kinase solution are pipetted in (containing 0.5 ng B-Raf (V600E)-kinase, e.g. from Upstate) in 20 mM Tris-HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA, 0.286 mM sodium orthovanadate, 10% glycerol, 1 mg/mL bovine serum albumin, 1 mM dithiothreitol) and the mixture is incubated for 1 h at RT with shaking. The kinase reaction is started by the addition of 20 uL/well ATP solution [final concentration: 250 uM ATP, 30 mM Tris-HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mM magnesium acetate, 0.1 mM EGTA.
Measurement: IC50 = 41 nM (pChEMBL 7.389999866485596)
Descriptors: MW 542.62, ALogP 3.5, HBA 9, HBD 2, PSA 117.93, QED 0.35
Compound (SMILES): Cn1c(=O)c(Sc2ccc(F)cc2)cc2cnc(Nc3ccc4[nH]ccc4c3)nc21
InChIKey: FJECSOOLAWUZAB-UHFFFAOYSA-N
Target: Casein kinase I isoform epsilon (SINGLE PROTEIN), Homo sapiens
UniProt: P49674
Assay: Kinase Inhibition Assay: The compound of Example 39, 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one, was subjected to a kinase inhibition assay for the kinases. Compounds were tested in 5 dose IC50 mode with 10-fold serial dilution starting at 10 μM. Staurosporine, a known protein kinase inhibitor, was tested in 5-dose IC50 mode with 3-fold serial dilution starting at 20 μM. Reactions were carried out in 10 μM ATP. The results are shown in Table 5. The results show that the compound of Example 39 is a kinase inhibitor highly selective for the kinase Plk2.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 417.47, ALogP 4.84, HBA 6, HBD 2, PSA 75.6, QED 0.44
Compound (SMILES): CS(=O)(=O)c1cc(-c2ccc(C[C@@H](C#N)NC(=O)C34CCC(CC3)CN4)c(F)c2)ccc1C#N
InChIKey: WTFPMTZBRYAXAT-MHVXWQKQSA-N
Target: Dipeptidyl peptidase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53634
Assay: Inhbition Assay: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ug/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) and incubating for 5 min at room temperature.Five uL test compound (final concentration 0.1 nM to 100 uM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of DPPI in MES buffer (final concentration 0.0125 ng/uL) and incubated for 10 min. Then, 5 uL of substrate in MES buffer (final concentration 50 uM) were added. The microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 uL of Gly-Phe-DMK in MES-buffer (final concentration 1 uM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Measurement: IC50 = 10.9 nM (pChEMBL 7.960000038146973)
Descriptors: MW 480.57, ALogP 2.85, HBA 6, HBD 2, PSA 122.85, QED 0.66
Compound (SMILES): CN1C(=O)Cc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C45CCC(CC4)CN5)cc3)cc21
InChIKey: FLUKFHZYRHSYID-ZRTADFRUSA-N
Target: Dipeptidyl peptidase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53634
Assay: Inhbition Assay: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ug/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) and incubating for 5 min at room temperature.Five uL test compound (final concentration 0.1 nM to 100 uM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of DPPI in MES buffer (final concentration 0.0125 ng/uL) and incubated for 10 min. Then, 5 uL of substrate in MES buffer (final concentration 50 uM) were added. The microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 uL of Gly-Phe-DMK in MES-buffer (final concentration 1 uM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Measurement: IC50 = 17.1 nM (pChEMBL 7.769999980926514)
Descriptors: MW 428.54, ALogP 2.96, HBA 4, HBD 2, PSA 85.23, QED 0.77
Compound (SMILES): CS(=O)(=O)c1cc(-c2ccc(C[C@@H](C#N)NC(=O)C34CCC(CC3)CN4)cc2)ccc1C#N
InChIKey: KMWDHMSUUMKGQS-JMNVSDKBSA-N
Target: Dipeptidyl peptidase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53634
Assay: Inhbition Assay: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ug/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) and incubating for 5 min at room temperature.Five uL test compound (final concentration 0.1 nM to 100 uM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of DPPI in MES buffer (final concentration 0.0125 ng/uL) and incubated for 10 min. Then, 5 uL of substrate in MES buffer (final concentration 50 uM) were added. The microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 uL of Gly-Phe-DMK in MES-buffer (final concentration 1 uM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Measurement: IC50 = 35.7 nM (pChEMBL 7.449999809265137)
Descriptors: MW 462.58, ALogP 2.71, HBA 6, HBD 2, PSA 122.85, QED 0.68
Compound (SMILES): CN1Cc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C45CCC(CC4)CN5)cc3)ccc2C1=O
InChIKey: NOSUEQLRRACAQS-ZRTADFRUSA-N
Target: Cathepsin K (SINGLE PROTEIN), Homo sapiens
UniProt: P43235
Assay: Inhbition Assay: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ug/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) and incubating for 5 min at room temperature.Five uL test compound (final concentration 0.1 nM to 100 uM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of DPPI in MES buffer (final concentration 0.0125 ng/uL) and incubated for 10 min. Then, 5 uL of substrate in MES buffer (final concentration 50 uM) were added. The microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 uL of Gly-Phe-DMK in MES-buffer (final concentration 1 uM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Measurement: IC50 = 6300 nM (pChEMBL 5.199999809265137)
Descriptors: MW 428.54, ALogP 3.02, HBA 4, HBD 2, PSA 85.23, QED 0.77
Compound (SMILES): CN1C(=O)Cc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@]45CC[C@H](CN4)C5)cc3)cc21
InChIKey: UZYGCBGSFBCHRH-ADSMNUKGSA-N
Target: Dipeptidyl peptidase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53634
Assay: Inhbition Assay: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ug/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) and incubating for 5 min at room temperature.Five uL test compound (final concentration 0.1 nM to 100 uM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of DPPI in MES buffer (final concentration 0.0125 ng/uL) and incubated for 10 min. Then, 5 uL of substrate in MES buffer (final concentration 50 uM) were added. The microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 uL of Gly-Phe-DMK in MES-buffer (final concentration 1 uM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Measurement: IC50 = 221 nM (pChEMBL 6.659999847412109)
Descriptors: MW 414.51, ALogP 2.57, HBA 4, HBD 2, PSA 85.23, QED 0.79
Compound (SMILES): CN1C(=O)Cc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C45CCOC(CCN4)C5)cc3)cc21
InChIKey: SVWPHMXSWNIINX-OKFDZGCWSA-N
Target: Dipeptidyl peptidase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53634
Assay: Inhbition Assay: The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ug/ml, respectively), and then activated by mixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) and incubating for 5 min at room temperature.Five uL test compound (final concentration 0.1 nM to 100 uM) in aqua bidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uL of DPPI in MES buffer (final concentration 0.0125 ng/uL) and incubated for 10 min. Then, 5 uL of substrate in MES buffer (final concentration 50 uM) were added. The microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 uL of Gly-Phe-DMK in MES-buffer (final concentration 1 uM). The fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
Measurement: IC50 = 227.8 nM (pChEMBL 6.639999866485596)
Descriptors: MW 444.54, ALogP 2.33, HBA 5, HBD 2, PSA 94.46, QED 0.74