lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): C[C@@H]1CC(=O)Nc2cccc(-c3cccc(OCc4ccccc4)c3)c2N1
InChIKey: XKIQUMIGIBMUJB-MRXNPFEDSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: BRD4 AlphaLisa Binding Assay: His/Flag epitope tagged BRD4 BD142-168 was cloned, expressed, and purified to. BRD4 binding and inhibition was assessed by monitoring the engagement of biotinylated H4-tetraacetyl peptide (New England Peptide, NEP2069-1/13) with the target using the AlphaLisa technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD4(BD1) (30 nM final) was combined with peptide (200 nM final) in 40 mM HEPES (pH 7.0), 40 mM NaCl, 1 mM DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 1.2% DMSO) or compound dilution series in DMSO. After 20 minutes incubation at room temperature Alpha streptavidin donor beads and AlphaLisa anti-Flag acceptor beads were added to a final concentration of 10 ug/mL each. After three hours equilibration plates were read on an Envision instrument and IC50s calculated using a four parameter non-linear curve fit.
Measurement: IC50 = 1722 nM (pChEMBL 5.760000228881836)
Descriptors: MW 358.44, ALogP 5.08, HBA 3, HBD 2, PSA 50.36, QED 0.68
Compound (SMILES): C[C@@H]1CC(=O)Nc2cccc(-c3ccc4c(c3)c(C3CC3)nn4C)c2N1
InChIKey: RUOHSEWJRWMCPQ-GFCCVEGCSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: BRD4 AlphaLisa Binding Assay: His/Flag epitope tagged BRD4 BD142-168 was cloned, expressed, and purified to. BRD4 binding and inhibition was assessed by monitoring the engagement of biotinylated H4-tetraacetyl peptide (New England Peptide, NEP2069-1/13) with the target using the AlphaLisa technology (Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD4(BD1) (30 nM final) was combined with peptide (200 nM final) in 40 mM HEPES (pH 7.0), 40 mM NaCl, 1 mM DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in the presence of DMSO (final 1.2% DMSO) or compound dilution series in DMSO. After 20 minutes incubation at room temperature Alpha streptavidin donor beads and AlphaLisa anti-Flag acceptor beads were added to a final concentration of 10 ug/mL each. After three hours equilibration plates were read on an Envision instrument and IC50s calculated using a four parameter non-linear curve fit.
Measurement: IC50 = 4028 nM (pChEMBL 5.389999866485596)
Descriptors: MW 346.43, ALogP 4.26, HBA 4, HBD 2, PSA 58.95, QED 0.73
Compound (SMILES): C[C@@H]1CC(=O)Nc2cccc(-c3ccc4c(c3)c(-c3cnn(C)c3)nn4C)c2N1
InChIKey: BFTKDWYIRJGJCA-CYBMUJFWSA-N
Target: CREB-binding protein (SINGLE PROTEIN), Homo sapiens
UniProt: Q92793
Assay: Inhibition of Halo-tagged histone H3.3 binding to CBP (unknown origin) expressed in HEK293 cells after overnight incubation by luciferase reporter gene based BRET assay
Measurement: EC50 = 300 nM (pChEMBL 6.519999980926514)
Descriptors: MW 386.46, ALogP 3.78, HBA 6, HBD 2, PSA 76.77, QED 0.55
Compound (SMILES): CCCCc1cc(-c2c[nH]c3ncccc23)nc(N)n1
InChIKey: JPZHGBZYRNZXPJ-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3K gamma (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 267.34, ALogP 2.94, HBA 4, HBD 2, PSA 80.48, QED 0.76
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4ccc(N)nc4)cc23)nc(N)n1
InChIKey: OAHPBQMQMWLROW-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3K gamma (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 331.38, ALogP 2.81, HBA 6, HBD 3, PSA 119.39, QED 0.53
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4ccco4)cc23)nc(N)n1
InChIKey: FUJVXFVFHBMKTN-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 305.34, ALogP 3.42, HBA 5, HBD 2, PSA 93.62, QED 0.6
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4cn[nH]c4)cc23)nc(N)n1
InChIKey: IVPOFDCEHKLJIL-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3K gamma (unknown origin)
Measurement: IC50 = 7000 nM (pChEMBL 5.159999847412109)
Descriptors: MW 305.35, ALogP 2.55, HBA 5, HBD 3, PSA 109.16, QED 0.54
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4ccn[nH]4)cc23)nc(N)n1
InChIKey: ALKWULYFERWLTF-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3K gamma (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 305.35, ALogP 2.55, HBA 5, HBD 3, PSA 109.16, QED 0.54
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4cnn(CCN(C)C)c4)cc23)nc(N)n1
InChIKey: SXIKIZKLTINDTH-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3K gamma (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 376.47, ALogP 2.59, HBA 7, HBD 2, PSA 101.54, QED 0.54
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4cnn(CC(C)C)c4)cc23)nc(N)n1
InChIKey: UCPCTKLUCPTSCC-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3K gamma (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 361.45, ALogP 3.68, HBA 6, HBD 2, PSA 98.3, QED 0.56
Compound (SMILES): CCCCc1cc(-c2c[nH]c3ncc(-c4cnn(C5CCNCC5)c4)cc23)nc(N)n1
InChIKey: ZIZZRQUDLPLGFQ-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 = 4000 nM (pChEMBL 5.400000095367432)
Descriptors: MW 416.53, ALogP 3.73, HBA 7, HBD 3, PSA 110.33, QED 0.44
Compound (SMILES): CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)c(O)c1
InChIKey: PFNIPVRYLSNESB-UHFFFAOYSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Agonist activity at GAL4 fused LXRbeta-LBD (unknown origin) transfected in CHOK1 cells after 24 hrs by luciferase reporter gene assay
Measurement: EC50 = 2900 nM (pChEMBL 5.539999961853027)
Descriptors: MW 683.6, ALogP 6.28, HBA 8, HBD 3, PSA 138.29, QED 0.12
Compound (SMILES): CC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
InChIKey: GHBSEBSMHLRBTM-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR Del19/T790M double mutant (unknown origin) expressed in mouse BaF/3 cells assessed as cell growth inhibition after 72 hrs by MTS assay
Measurement: IC50 = 2280 nM (pChEMBL 5.639999866485596)
Descriptors: MW 436.87, ALogP 5.7, HBA 5, HBD 2, PSA 76.14, QED 0.4
Compound (SMILES): O=C(NCCN1CCCCC1)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
InChIKey: ADFNBVCUNARPQJ-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR Del19/T790M double mutant (unknown origin) expressed in mouse BaF/3 cells assessed as cell growth inhibition after 72 hrs by MTS assay
Measurement: IC50 = 2380 nM (pChEMBL 5.619999885559082)
Descriptors: MW 549.05, ALogP 6.35, HBA 6, HBD 3, PSA 91.41, QED 0.23
Compound (SMILES): Fc1cccc(COc2ccc(Nc3ncnc4ccc(NC(=S)NCCN5CCCCC5)cc34)cc2Cl)c1
InChIKey: XKKGXXXXAQKVRW-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR Del19/T790M double mutant (unknown origin) expressed in mouse BaF/3 cells assessed as cell growth inhibition after 72 hrs by MTS assay
Measurement: IC50 = 2310 nM (pChEMBL 5.639999866485596)
Descriptors: MW 565.12, ALogP 6.52, HBA 6, HBD 3, PSA 74.34, QED 0.2
Compound (SMILES): COC(=O)c1cc2cc(NCc3cc(NC(=O)c4cc(-n5cnc(C)c5)cc(C(F)(F)F)c4)ccc3C)cnc2[nH]1
InChIKey: PGQWALGGBUYLQF-UHFFFAOYSA-N
Target: Proto-oncogene tyrosine-protein kinase Src (SINGLE PROTEIN), Homo sapiens
UniProt: P12931
Assay: Inhibition of full length His-tagged human recombinant cSRC expressed in baculovirus using Fluorescein-Poly GT as substrate
Measurement: IC50 = 40 nM (pChEMBL 7.400000095367432)
Descriptors: MW 562.55, ALogP 6.04, HBA 7, HBD 3, PSA 113.93, QED 0.21
Compound (SMILES): CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)c(C(=O)NCc3ccccn3)c2)NC(=O)N1
InChIKey: BLMBNKDQXGINRE-UHFFFAOYSA-N
Target: G protein-coupled receptor kinase 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P34947
Assay: Inhibition of human GRK5 C474S mutant using porcine brain tubulin as substrate incubated for 3 to 5 mins by [gamma32P]ATP based radiometric assay
Measurement: IC50 = 220 nM (pChEMBL 6.659999847412109)
Descriptors: MW 499.51, ALogP 3.29, HBA 5, HBD 5, PSA 140.9, QED 0.28
Compound (SMILES): CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)c(C(=O)NCCc3ccncc3)c2)NC(=O)N1
InChIKey: GJTSGDBPSODHKH-UHFFFAOYSA-N
Target: G protein-coupled receptor kinase 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P34947
Assay: Assays for Inhibition of GRKs: GRK1, 2 and 5 kinetic assays were conducted in a buffer containing 20 mM HEPES pH 7.0, 5 μM ATP, 2 mM MgCl2, and 0.025% DDM with 50 nM GRK and either 500 nM bROS or 500 nM soluble substrate tubulin in 5 min reactions. The low salt concentration and DDM were used to maximize GRK activity and disrupt small molecule aggregates from forming, respectively. Reactions were quenched with SDS loading buffer, separated via SDS-PAGE, dried and exposed with a phosphorimaging screen prior to quantification via Typhoon imager, as previously reported (see Thal et al., ACS Chemical Biology 7(11):1830-1839 (2012)). Data was analyzed and inhibition curves were fit via GraphPad Prism.
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 513.53, ALogP 3.34, HBA 5, HBD 5, PSA 140.9, QED 0.26
Compound (SMILES): CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)c(C(=O)NCc3nccc4ccccc34)c2)NC(=O)N1
InChIKey: UGYAZGXSMRGKRD-UHFFFAOYSA-N
Target: Beta-adrenergic receptor kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P25098
Assay: Assays for Inhibition of GRKs: GRK1, 2 and 5 kinetic assays were conducted in a buffer containing 20 mM HEPES pH 7.0, 5 μM ATP, 2 mM MgCl2, and 0.025% DDM with 50 nM GRK and either 500 nM bROS or 500 nM soluble substrate tubulin in 5 min reactions. The low salt concentration and DDM were used to maximize GRK activity and disrupt small molecule aggregates from forming, respectively. Reactions were quenched with SDS loading buffer, separated via SDS-PAGE, dried and exposed with a phosphorimaging screen prior to quantification via Typhoon imager, as previously reported (see Thal et al., ACS Chemical Biology 7(11):1830-1839 (2012)). Data was analyzed and inhibition curves were fit via GraphPad Prism.
Measurement: IC50 = 2600 nM (pChEMBL 5.579999923706055)
Descriptors: MW 549.57, ALogP 4.45, HBA 5, HBD 5, PSA 140.9, QED 0.21
Compound (SMILES): COc1cccc(OC)c1CNC(=O)c1cc(C2NC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]ncc3c2)ccc1F
InChIKey: KQJWWWZXJNOLQF-UHFFFAOYSA-N
Target: G protein-coupled receptor kinase 5 (SINGLE PROTEIN), Bos taurus
UniProt: P43249
Assay: Inhibition of bovine GRK5 after 5 mins after 5 mins in presence of ATP by phosphorimaging assay
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 558.57, ALogP 3.92, HBA 6, HBD 5, PSA 146.47, QED 0.22
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N3CCCC3)c2n1
InChIKey: XPELYRINMWSZIB-UHFFFAOYSA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P20248
Assay: Inhibition of human full length recombinant His-tagged CDK2/CyclinA expressed in baculovirus using 5FAMQSPKKG-CONH2 as substrate after 60 mins
Measurement: Ki = 1420 nM (pChEMBL 5.849999904632568)
Descriptors: MW 401.47, ALogP 3.78, HBA 8, HBD 1, PSA 80.99, QED 0.54
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC(C)C)c2n1
InChIKey: QZZFLPGPIFLIDL-UHFFFAOYSA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P20248
Assay: Inhibition of human full length recombinant His-tagged CDK2/CyclinA expressed in baculovirus using 5FAMQSPKKG-CONH2 as substrate after 60 mins
Measurement: Ki = 430 nM (pChEMBL 6.369999885559082)
Descriptors: MW 403.49, ALogP 4.25, HBA 8, HBD 2, PSA 89.78, QED 0.48
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NC3CCCCC3)c2n1
InChIKey: DIBCUQSRSKMAFL-UHFFFAOYSA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P20248
Assay: Inhibition of human full length recombinant His-tagged CDK2/CyclinA expressed in baculovirus using 5FAMQSPKKG-CONH2 as substrate after 60 mins
Measurement: Ki = 100 nM (pChEMBL 7)
Descriptors: MW 429.53, ALogP 4.92, HBA 8, HBD 2, PSA 89.78, QED 0.45
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC3CC3)c2n1
InChIKey: RNRUHOJYKQGQGN-UHFFFAOYSA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P20248
Assay: Inhibition of human full length recombinant His-tagged CDK2/CyclinA expressed in baculovirus using 5FAMQSPKKG-CONH2 as substrate after 60 mins
Measurement: Ki = 540 nM (pChEMBL 6.269999980926514)
Descriptors: MW 401.47, ALogP 4, HBA 8, HBD 2, PSA 89.78, QED 0.48
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
InChIKey: WSTCEYSBWKYEDE-UHFFFAOYSA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P20248
Assay: Inhibition of human full length recombinant His-tagged CDK2/CyclinA expressed in baculovirus using 5FAMQSPKKG-CONH2 as substrate after 60 mins
Measurement: Ki = 230 nM (pChEMBL 6.639999866485596)
Descriptors: MW 417.52, ALogP 4.64, HBA 8, HBD 2, PSA 89.78, QED 0.47
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N[C@H](C)C(C)(C)C)c2n1
InChIKey: XTJZKALDRPVFSN-OAHLLOKOSA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P20248
Assay: Inhibition of human full length recombinant His-tagged CDK2/CyclinA expressed in baculovirus using 5FAMQSPKKG-CONH2 as substrate after 60 mins
Measurement: Ki = 240 nM (pChEMBL 6.619999885559082)
Descriptors: MW 431.54, ALogP 5.02, HBA 8, HBD 2, PSA 89.78, QED 0.44
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N[C@@H](C)C(C)(C)C)c2n1
InChIKey: XTJZKALDRPVFSN-HNNXBMFYSA-N
Target: Mitogen-activated protein kinase 8 (SINGLE PROTEIN), Homo sapiens
UniProt: P45983
Assay: Inhibition of human full length recombinant His-tagged JNK1 expressed in baculovirus by lanthascreen assay
Measurement: IC50 = 110 nM (pChEMBL 6.960000038146973)
Descriptors: MW 431.54, ALogP 5.02, HBA 8, HBD 2, PSA 89.78, QED 0.44
Compound (SMILES): CC(C)=CCC1=C(O)[C@](O)(CC=C(C)C)C(=O)C(C(=O)CC(C)C)=C1O
InChIKey: VMSLCPKYRPDHLN-OAQYLSRUSA-N
Target: Aldo-keto reductase family 1 member B10 (SINGLE PROTEIN), Homo sapiens
UniProt: O60218
Assay: Inhibition of AKR1B10 (unknown origin)
Measurement: IC50 = 1940 nM (pChEMBL 5.710000038146973)
Descriptors: MW 362.47, ALogP 4.25, HBA 5, HBD 3, PSA 94.83, QED 0.46
Compound (SMILES): CS(=O)(=O)c1cccc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C(c3ccccc3)C2)c1
InChIKey: CTCGRQVHZGKQJF-UHFFFAOYSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Displacement of [3H]TO901317 from LXRbeta ligand binding domain (unknown origin) after 30 mins by liquid scintillation counting
Measurement: Ki > 2500 nM (pChEMBL 5.6020002365112305)
Descriptors: MW 475.54, ALogP 4.57, HBA 5, HBD 0, PSA 53.51, QED 0.54
Compound (SMILES): CS(=O)(=O)c1cccc(N2CCN(c3nccc(C(F)(F)F)n3)C(c3ccccc3)C2)c1
InChIKey: GWLPLKIBBKZUGZ-UHFFFAOYSA-N
Target: Oxysterols receptor LXR-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q13133
Assay: Agonist activity at human LXRalpha ligand binding domain(167 to 447 residues) transfected in HEK293 cells after 16 hrs by Gal4-luciferase reporter gene assay
Measurement: EC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 462.5, ALogP 3.97, HBA 6, HBD 0, PSA 66.4, QED 0.58
Compound (SMILES): CC(C)[C@@H]1CN(c2cccc(S(C)(=O)=O)c2)CCN1c1nccc(C(F)(F)F)n1
InChIKey: XVRHEEOCNTZUNF-INIZCTEOSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Human LXRalpha and LXRbeta Coactivator Recruitment FRET Assay: This assay is based on the ability of the LXR-LBDs (LXRα and LXRβ) to recruit and interact with a co-activator peptide. This assay was run in agonist mode, to characterize compounds of the invention that exhibit LXR agonist activity, and in antagonist mode to characterize compounds of the invention having LXR antagonist activity and which cause a concentration-dependent release of the co-activator peptide in the presence of the full LXR agonist T0901317. The interaction between glutathione S-transferase (GST)-tagged, recombinant human LXRα-LBD or LXRβ-LBD and fluorescein-conjugated co-activator peptide SRC2-3 (Cat# PV4588, Life Technologies, Grand Island, N.Y.) was measured via time resolved-fluorescence resonance energy transfer (TR-FRET). The assay was performed in 96-well half-area black Opti-plates (Cat# 3686, Corning, Lowell, Mass.) in 20 mM TRIS-HCl buffer, pH 8, containing 150 mM NaCl and 5 mM DDT in a total volume of 80 μL. Test compounds were dissolved in DMSO, and semi-log (3.162×) serial dilutions were also prepared in DMSO, as 40× solutions.
Measurement: EC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 428.48, ALogP 3.25, HBA 6, HBD 0, PSA 66.4, QED 0.74
Compound (SMILES): CC(C)[C@@H]1CN(c2ccc(F)c(S(C)(=O)=O)c2)CCN1c1nccc(C(F)(F)F)n1
InChIKey: YTEDTWJJQBCOTI-HNNXBMFYSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Human LXRalpha and LXRbeta Coactivator Recruitment FRET Assay: This assay is based on the ability of the LXR-LBDs (LXRα and LXRβ) to recruit and interact with a co-activator peptide. This assay was run in agonist mode, to characterize compounds of the invention that exhibit LXR agonist activity, and in antagonist mode to characterize compounds of the invention having LXR antagonist activity and which cause a concentration-dependent release of the co-activator peptide in the presence of the full LXR agonist T0901317. The interaction between glutathione S-transferase (GST)-tagged, recombinant human LXRα-LBD or LXRβ-LBD and fluorescein-conjugated co-activator peptide SRC2-3 (Cat# PV4588, Life Technologies, Grand Island, N.Y.) was measured via time resolved-fluorescence resonance energy transfer (TR-FRET). The assay was performed in 96-well half-area black Opti-plates (Cat# 3686, Corning, Lowell, Mass.) in 20 mM TRIS-HCl buffer, pH 8, containing 150 mM NaCl and 5 mM DDT in a total volume of 80 μL. Test compounds were dissolved in DMSO, and semi-log (3.162×) serial dilutions were also prepared in DMSO, as 40× solutions.
Measurement: EC50 = 6 nM (pChEMBL 8.220000267028809)
Descriptors: MW 446.47, ALogP 3.39, HBA 6, HBD 0, PSA 66.4, QED 0.67
Compound (SMILES): CC(C)[C@@H]1CN(c2ccc(F)c(S(C)(=O)=O)c2)CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
InChIKey: HXOUVMGQDQYWNM-KRWDZBQOSA-N
Target: Oxysterols receptor LXR-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q13133
Assay: LXR alpha/beta Radioligand Binding Assay: Compounds of the invention were assessed in a competition binding assay where different concentrations of compounds were incubated with the LXR ligand binding domain (LBD) in the presence of radiolabeled LXR ligand [3H]TO901317. The amount of the LXR-LBD that complexed with [3H]T0901317 was measured by scintillation proximity assay (SPA) employing non-specific binding of LXR-LBD to poly-lysine coated Yttrium silicate beads. Partially purified LXR α or β LBD protein (15-45 nM) was incubated at rt for 30 min with 15 nM [3H]TO901317 (25-40 Ci/mmol) and different concentrations of test compounds in 80 μL of phosphate buffered saline (PBS) buffer containing 2.5% DMSO, 1% glycerol, 2 mM EDTA, 2 mM CHAPS and 5 mM DTT in 96-well plates. Poly-lysine SPA beads (50 μg) were added to each well and the total volume was adjusted to 120 μL. The plates were shaken on an orbital shaker for 20 min and then allowed to settle for 10 more min at rt before a brief centrifugation at 2,000 rpm for 1 min. The SPA signal was measured on a MicroBeta® liquid scintillation counter (Perkin Elmer, Waltham, Mass.), and the results were used for calculating IC50 values based on the total binding (DMSO control) and non-specific binding (5 μM of unlabeled TO901317) controls. The Ki values were calculated according to equation 1, where [RL] is the final concentration of [3H]TO901317 in the assay, and the Kd values of 20 nM and 10 nM of TO901317 for LBDs of LXRα and LXRβ, respectively, were determined by direct titration of the radioligand with these proteins.
Measurement: Ki = 487 nM (pChEMBL 6.309999942779541)
Descriptors: MW 504.55, ALogP 3.62, HBA 7, HBD 1, PSA 86.63, QED 0.62
Compound (SMILES): CC(C)[C@@H]1CN(c2ccc(CO)c(S(C)(=O)=O)c2)CCN1c1ncc(CO)c(C(F)(F)F)n1
InChIKey: FPVIRRAMNBCEDK-KRWDZBQOSA-N
Target: Oxysterols receptor LXR-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q13133
Assay: Displacement of radiolabeled T0901317 from LXRalpha LBD (unknown origin)
Measurement: Ki = 81 nM (pChEMBL 7.090000152587891)
Descriptors: MW 488.53, ALogP 2.23, HBA 8, HBD 2, PSA 106.86, QED 0.64
Compound (SMILES): CS(=O)(=O)c1cc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)ccc1CO
InChIKey: NLDOCDWHNYIGKV-UHFFFAOYSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Displacement of [3H]TO901317 from LXRbeta ligand binding domain (unknown origin) after 30 mins by liquid scintillation counting
Measurement: Ki = 1.3 nM (pChEMBL 8.890000343322754)
Descriptors: MW 595.69, ALogP 5.72, HBA 6, HBD 1, PSA 91.75, QED 0.27
Compound (SMILES): O=c1c(OCCN2CCn3c2nc2ccccc23)cn(CC2CC2)nc1-c1ccnn1-c1ccccc1
InChIKey: PMQGNBOUOYQTPQ-UHFFFAOYSA-N
Target: cGMP-specific 3',5'-cyclic phosphodiesterase (SINGLE PROTEIN), Homo sapiens
UniProt: O76074
Assay: Inhibition of human PDE5A1
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 493.57, ALogP 3.75, HBA 9, HBD 0, PSA 83, QED 0.33
Compound (SMILES): CN(C/C=C/c1ccc(C(F)(F)F)cc1)Cc1cccc2ccoc12.Cl
InChIKey: UMJCCCZKGYJSIX-BJILWQEISA-N
Target: 4,4'-diapophytoene desaturase (4,4'-diaponeurosporene-forming) (SINGLE PROTEIN), Staphylococcus aureus (strain Newman)
UniProt: O07855
Assay: Inhibition of Staphylococcus aureus Newman 6His-tagged CrtN expressed in Escherichia coli BL21 (DE3)/pET28a::CrtN assessed as reduction in staphyloxanthin levels using diapophytoene as substrate after overnight incubation by spectrophotometric analysis
Measurement: IC50 = 300 nM (pChEMBL 6.519999980926514)
Descriptors: MW 345.36, ALogP 5.6, HBA 2, HBD 0, PSA 16.38, QED 0.6
Compound (SMILES): N[C@@H](COP(=O)(O)O[C@@H]1CCCO[C@@H]1COC(=O)CCc1ccccc1OCc1cccc(Oc2ccccc2)c1)C(=O)O
InChIKey: BIGHQMOUQYMHQN-WIIGKZCBSA-N
Target: Probable G-protein coupled receptor 34 (SINGLE PROTEIN), Mus musculus
UniProt: Q9R1K6
Assay: Agonist activity at mouse GPR34 expressed in HEK293 cells co-transfected with AP-TGFalpha/chimeric Galphaq/i1 assessed as induction of ectodomain shedding of membrane bound AP-TGFalpha after 1 hr
Measurement: EC50 = 180 nM (pChEMBL 6.75)
Descriptors: MW 629.6, ALogP 4.63, HBA 10, HBD 3, PSA 173.07, QED 0.15
Compound (SMILES): CC1(C)OCCn2c1nc1c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
InChIKey: LGWACEZVCMBSKW-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of P13Kdelta (unknown origin)
Measurement: IC50 = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 382.43, ALogP 0.97, HBA 10, HBD 1, PSA 117.1, QED 0.69
Compound (SMILES): FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)cn1
InChIKey: JGWRKYUXBBNENE-UHFFFAOYSA-N
Target: Acyl-CoA dehydrogenase family member 10 (SINGLE PROTEIN), Homo sapiens
UniProt: Q6JQN1
Assay: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
Measurement: Kd > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 417.82, ALogP 5.23, HBA 4, HBD 2, PSA 66.49, QED 0.47
Compound (SMILES): CN(C)CCCn1cc(-c2ccc3c(c2)-c2[nH]c4cc(-c5cn[nH]c5)ccc4c2C3=O)cn1
InChIKey: JRJKATLTRNXYCE-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Competitive inhibition of FLT3 D835Y mutant (unknown origin) in presence of ATP
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 436.52, ALogP 4.58, HBA 5, HBD 2, PSA 82.6, QED 0.4
Compound (SMILES): C[C@@H]1CC(=O)Nc2cccc(-c3ccc4c(c3)c(-c3cnn(C)c3)nn4C)c2N1
InChIKey: BFTKDWYIRJGJCA-CYBMUJFWSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: Displacement of biotinylated ligand from recombinant His-tagged BRD4 bromodomain-1 (unknown origin) incubated for 10 mins by TR-FRET assay
Measurement: IC50 = 11000 nM (pChEMBL 4.960000038146973)
Descriptors: MW 386.46, ALogP 3.78, HBA 6, HBD 2, PSA 76.77, QED 0.55
Compound (SMILES): CCCCc1cc(-c2c[nH]c3ncccc23)nc(N)n1
InChIKey: JPZHGBZYRNZXPJ-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 267.34, ALogP 2.94, HBA 4, HBD 2, PSA 80.48, QED 0.76
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4ccc(N)nc4)cc23)nc(N)n1
InChIKey: OAHPBQMQMWLROW-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 331.38, ALogP 2.81, HBA 6, HBD 3, PSA 119.39, QED 0.53
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4cn[nH]c4)cc23)nc(N)n1
InChIKey: IVPOFDCEHKLJIL-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 305.35, ALogP 2.55, HBA 5, HBD 3, PSA 109.16, QED 0.54
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4ccn[nH]4)cc23)nc(N)n1
InChIKey: ALKWULYFERWLTF-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 305.35, ALogP 2.55, HBA 5, HBD 3, PSA 109.16, QED 0.54
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4cnn(CCN(C)C)c4)cc23)nc(N)n1
InChIKey: SXIKIZKLTINDTH-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 376.47, ALogP 2.59, HBA 7, HBD 2, PSA 101.54, QED 0.54
Compound (SMILES): CCc1cc(-c2c[nH]c3ncc(-c4cnn(CC(C)C)c4)cc23)nc(N)n1
InChIKey: UCPCTKLUCPTSCC-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Inhibition of PI3K delta (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 361.45, ALogP 3.68, HBA 6, HBD 2, PSA 98.3, QED 0.56
Compound (SMILES): COC(=O)c1cc2cc(NCc3cc(NC(=O)c4cc(-n5cnc(C)c5)cc(C(F)(F)F)c4)ccc3C)cnc2[nH]1
InChIKey: PGQWALGGBUYLQF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Yes (SINGLE PROTEIN), Homo sapiens
UniProt: P07947
Assay: Inhibition of GST-tagged full length human recombinant YES expressed in baculovirus using Fluorescein-Poly GT as substrate
Measurement: IC50 = 44 nM (pChEMBL 7.360000133514404)
Descriptors: MW 562.55, ALogP 6.04, HBA 7, HBD 3, PSA 113.93, QED 0.21
Compound (SMILES): CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)c(C(=O)NCCc3ccncc3)c2)NC(=O)N1
InChIKey: GJTSGDBPSODHKH-UHFFFAOYSA-N
Target: Rho-associated protein kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13464
Assay: Assays for Inhibition of ROCK: Rho-associated coiled-coil kinase (ROCK) assays were performed with the ADP-Glo system using 0.1 μg ROCK1 and 1 μg S6K substrate, and 100 μM ATP for 60 min prior to addition of ADP-GLO Reagent, and allowed to incubate for an additional 40 min prior to the addition of the Kinase Detection Reagent and imaging on a PHERASTAR system.
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 513.53, ALogP 3.34, HBA 5, HBD 5, PSA 140.9, QED 0.26
Compound (SMILES): CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)c(C(=O)NCc3nccc4ccccc34)c2)NC(=O)N1
InChIKey: UGYAZGXSMRGKRD-UHFFFAOYSA-N
Target: G protein-coupled receptor kinase 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P34947
Assay: Assays for Inhibition of GRKs: GRK1, 2 and 5 kinetic assays were conducted in a buffer containing 20 mM HEPES pH 7.0, 5 μM ATP, 2 mM MgCl2, and 0.025% DDM with 50 nM GRK and either 500 nM bROS or 500 nM soluble substrate tubulin in 5 min reactions. The low salt concentration and DDM were used to maximize GRK activity and disrupt small molecule aggregates from forming, respectively. Reactions were quenched with SDS loading buffer, separated via SDS-PAGE, dried and exposed with a phosphorimaging screen prior to quantification via Typhoon imager, as previously reported (see Thal et al., ACS Chemical Biology 7(11):1830-1839 (2012)). Data was analyzed and inhibition curves were fit via GraphPad Prism.
Measurement: IC50 = 5400 nM (pChEMBL 5.269999980926514)
Descriptors: MW 549.57, ALogP 4.45, HBA 5, HBD 5, PSA 140.9, QED 0.21
Compound (SMILES): COc1cccc(OC)c1CNC(=O)c1cc(C2NC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]ncc3c2)ccc1F
InChIKey: KQJWWWZXJNOLQF-UHFFFAOYSA-N
Target: Beta-adrenergic receptor kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P25098
Assay: Inhibition of GRK2 (unknown origin)
Measurement: IC50 = 20 nM (pChEMBL 7.699999809265137)
Descriptors: MW 558.57, ALogP 3.92, HBA 6, HBD 5, PSA 146.47, QED 0.22
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N3CCCC3)c2n1
InChIKey: XPELYRINMWSZIB-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Enzyme Inhibition Assay: The enzyme reaction (total volume 10 μl) was carried out in black 384-well low volume plates containing full length MPS1 (12.5 nM or 3 nM), fluorescent labelled peptide [known as H236, which has the sequence: 5FAM-DHTGFLTEYVATR-CONH2] (5 μM), ATP(10 μM), either DMSO (1% v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) and assay buffer (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM Orthovandate, 10 μM MgCl2, 1 μM DTT, Roche protease inhibitor). The reaction was carried out for 60 min at room temperature and stopped by the addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v) Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The plate was read on a Caliper EZ reader II (Caliper Life Sciences).
Measurement: IC50 = 8 nM (pChEMBL 8.100000381469727)
Descriptors: MW 401.47, ALogP 3.78, HBA 8, HBD 1, PSA 80.99, QED 0.54
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC(C)C)c2n1
InChIKey: QZZFLPGPIFLIDL-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Enzyme Inhibition Assay: The enzyme reaction (total volume 10 μl) was carried out in black 384-well low volume plates containing full length MPS1 (12.5 nM or 3 nM), fluorescent labelled peptide [known as H236, which has the sequence: 5FAM-DHTGFLTEYVATR-CONH2] (5 μM), ATP(10 μM), either DMSO (1% v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) and assay buffer (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM Orthovandate, 10 μM MgCl2, 1 μM DTT, Roche protease inhibitor). The reaction was carried out for 60 min at room temperature and stopped by the addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v) Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The plate was read on a Caliper EZ reader II (Caliper Life Sciences).
Measurement: IC50 = 8 nM (pChEMBL 8.100000381469727)
Descriptors: MW 403.49, ALogP 4.25, HBA 8, HBD 2, PSA 89.78, QED 0.48
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NC3CCCCC3)c2n1
InChIKey: DIBCUQSRSKMAFL-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Enzyme Inhibition Assay: The enzyme reaction (total volume 10 μl) was carried out in black 384-well low volume plates containing full length MPS1 (12.5 nM or 3 nM), fluorescent labelled peptide [known as H236, which has the sequence: 5FAM-DHTGFLTEYVATR-CONH2] (5 μM), ATP(10 μM), either DMSO (1% v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) and assay buffer (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM Orthovandate, 10 μM MgCl2, 1 μM DTT, Roche protease inhibitor). The reaction was carried out for 60 min at room temperature and stopped by the addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v) Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The plate was read on a Caliper EZ reader II (Caliper Life Sciences).
Measurement: IC50 = 9 nM (pChEMBL 8.050000190734863)
Descriptors: MW 429.53, ALogP 4.92, HBA 8, HBD 2, PSA 89.78, QED 0.45
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC3CC3)c2n1
InChIKey: RNRUHOJYKQGQGN-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Enzyme Inhibition Assay: The enzyme reaction (total volume 10 μl) was carried out in black 384-well low volume plates containing full length MPS1 (12.5 nM or 3 nM), fluorescent labelled peptide [known as H236, which has the sequence: 5FAM-DHTGFLTEYVATR-CONH2] (5 μM), ATP(10 μM), either DMSO (1% v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) and assay buffer (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM Orthovandate, 10 μM MgCl2, 1 μM DTT, Roche protease inhibitor). The reaction was carried out for 60 min at room temperature and stopped by the addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v) Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The plate was read on a Caliper EZ reader II (Caliper Life Sciences).
Measurement: IC50 = 6 nM (pChEMBL 8.220000267028809)
Descriptors: MW 401.47, ALogP 4, HBA 8, HBD 2, PSA 89.78, QED 0.48
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
InChIKey: WSTCEYSBWKYEDE-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Enzyme Inhibition Assay: The enzyme reaction (total volume 10 μl) was carried out in black 384-well low volume plates containing full length MPS1 (12.5 nM or 3 nM), fluorescent labelled peptide [known as H236, which has the sequence: 5FAM-DHTGFLTEYVATR-CONH2] (5 μM), ATP(10 μM), either DMSO (1% v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) and assay buffer (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM Orthovandate, 10 μM MgCl2, 1 μM DTT, Roche protease inhibitor). The reaction was carried out for 60 min at room temperature and stopped by the addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v) Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The plate was read on a Caliper EZ reader II (Caliper Life Sciences).
Measurement: IC50 = 8 nM (pChEMBL 8.100000381469727)
Descriptors: MW 417.52, ALogP 4.64, HBA 8, HBD 2, PSA 89.78, QED 0.47
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N[C@H](C)C(C)(C)C)c2n1
InChIKey: XTJZKALDRPVFSN-OAHLLOKOSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Enzyme Inhibition Assay: The enzyme reaction (total volume 10 μl) was carried out in black 384-well low volume plates containing full length MPS1 (12.5 nM or 3 nM), fluorescent labelled peptide [known as H236, which has the sequence: 5FAM-DHTGFLTEYVATR-CONH2] (5 μM), ATP(10 μM), either DMSO (1% v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) and assay buffer (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% BSA, 0.1 mM Orthovandate, 10 μM MgCl2, 1 μM DTT, Roche protease inhibitor). The reaction was carried out for 60 min at room temperature and stopped by the addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v) Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The plate was read on a Caliper EZ reader II (Caliper Life Sciences).
Measurement: IC50 = 9 nM (pChEMBL 8.050000190734863)
Descriptors: MW 431.54, ALogP 5.02, HBA 8, HBD 2, PSA 89.78, QED 0.44
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N[C@@H](C)C(C)(C)C)c2n1
InChIKey: XTJZKALDRPVFSN-HNNXBMFYSA-N
Target: Mitogen-activated protein kinase 9 (SINGLE PROTEIN), Homo sapiens
UniProt: P45984
Assay: Inhibition of human full length recombinant His-tagged JNK2 expressed in baculovirus by lanthascreen assay
Measurement: IC50 = 220 nM (pChEMBL 6.659999847412109)
Descriptors: MW 431.54, ALogP 5.02, HBA 8, HBD 2, PSA 89.78, QED 0.44
Compound (SMILES): CS(=O)(=O)c1cccc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C(c3ccccc3)C2)c1
InChIKey: CTCGRQVHZGKQJF-UHFFFAOYSA-N
Target: Oxysterols receptor LXR-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q13133
Assay: Agonist activity at human LXRalpha ligand binding domain(167 to 447 residues) transfected in HEK293 cells after 16 hrs by Gal4-luciferase reporter gene assay
Measurement: EC50 = 5375 nM (pChEMBL 5.269999980926514)
Descriptors: MW 475.54, ALogP 4.57, HBA 5, HBD 0, PSA 53.51, QED 0.54
Compound (SMILES): CS(=O)(=O)c1cccc(N2CCN(c3nccc(C(F)(F)F)n3)C(c3ccccc3)C2)c1
InChIKey: GWLPLKIBBKZUGZ-UHFFFAOYSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Agonist activity at human LXRbeta ligand binding domain(155 to 460 residues) transfected in HEK293 cells after 16 hrs by Gal4-luciferase reporter gene assay
Measurement: EC50 = 1289 nM (pChEMBL 5.889999866485596)
Descriptors: MW 462.5, ALogP 3.97, HBA 6, HBD 0, PSA 66.4, QED 0.58
Compound (SMILES): CC(C)[C@@H]1CN(c2ccc(F)c(S(C)(=O)=O)c2)CCN1c1nccc(C(F)(F)F)n1
InChIKey: YTEDTWJJQBCOTI-HNNXBMFYSA-N
Target: Oxysterols receptor LXR-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q13133
Assay: LXR alpha/beta Radioligand Binding Assay: Compounds of the invention were assessed in a competition binding assay where different concentrations of compounds were incubated with the LXR ligand binding domain (LBD) in the presence of radiolabeled LXR ligand [3H]TO901317. The amount of the LXR-LBD that complexed with [3H]T0901317 was measured by scintillation proximity assay (SPA) employing non-specific binding of LXR-LBD to poly-lysine coated Yttrium silicate beads. Partially purified LXR α or β LBD protein (15-45 nM) was incubated at rt for 30 min with 15 nM [3H]TO901317 (25-40 Ci/mmol) and different concentrations of test compounds in 80 μL of phosphate buffered saline (PBS) buffer containing 2.5% DMSO, 1% glycerol, 2 mM EDTA, 2 mM CHAPS and 5 mM DTT in 96-well plates. Poly-lysine SPA beads (50 μg) were added to each well and the total volume was adjusted to 120 μL. The plates were shaken on an orbital shaker for 20 min and then allowed to settle for 10 more min at rt before a brief centrifugation at 2,000 rpm for 1 min. The SPA signal was measured on a MicroBeta® liquid scintillation counter (Perkin Elmer, Waltham, Mass.), and the results were used for calculating IC50 values based on the total binding (DMSO control) and non-specific binding (5 μM of unlabeled TO901317) controls. The Ki values were calculated according to equation 1, where [RL] is the final concentration of [3H]TO901317 in the assay, and the Kd values of 20 nM and 10 nM of TO901317 for LBDs of LXRα and LXRβ, respectively, were determined by direct titration of the radioligand with these proteins.
Measurement: Ki = 91 nM (pChEMBL 7.039999961853027)
Descriptors: MW 446.47, ALogP 3.39, HBA 6, HBD 0, PSA 66.4, QED 0.67
Compound (SMILES): CC(C)[C@@H]1CN(c2ccc(F)c(S(C)(=O)=O)c2)CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
InChIKey: HXOUVMGQDQYWNM-KRWDZBQOSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: LXR alpha/beta Radioligand Binding Assay: Compounds of the invention were assessed in a competition binding assay where different concentrations of compounds were incubated with the LXR ligand binding domain (LBD) in the presence of radiolabeled LXR ligand [3H]TO901317. The amount of the LXR-LBD that complexed with [3H]T0901317 was measured by scintillation proximity assay (SPA) employing non-specific binding of LXR-LBD to poly-lysine coated Yttrium silicate beads. Partially purified LXR α or β LBD protein (15-45 nM) was incubated at rt for 30 min with 15 nM [3H]TO901317 (25-40 Ci/mmol) and different concentrations of test compounds in 80 μL of phosphate buffered saline (PBS) buffer containing 2.5% DMSO, 1% glycerol, 2 mM EDTA, 2 mM CHAPS and 5 mM DTT in 96-well plates. Poly-lysine SPA beads (50 μg) were added to each well and the total volume was adjusted to 120 μL. The plates were shaken on an orbital shaker for 20 min and then allowed to settle for 10 more min at rt before a brief centrifugation at 2,000 rpm for 1 min. The SPA signal was measured on a MicroBeta® liquid scintillation counter (Perkin Elmer, Waltham, Mass.), and the results were used for calculating IC50 values based on the total binding (DMSO control) and non-specific binding (5 μM of unlabeled TO901317) controls. The Ki values were calculated according to equation 1, where [RL] is the final concentration of [3H]TO901317 in the assay, and the Kd values of 20 nM and 10 nM of TO901317 for LBDs of LXRα and LXRβ, respectively, were determined by direct titration of the radioligand with these proteins.
Measurement: Ki = 14 nM (pChEMBL 7.849999904632568)
Descriptors: MW 504.55, ALogP 3.62, HBA 7, HBD 1, PSA 86.63, QED 0.62
Compound (SMILES): CC(C)[C@@H]1CN(c2ccc(CO)c(S(C)(=O)=O)c2)CCN1c1ncc(CO)c(C(F)(F)F)n1
InChIKey: FPVIRRAMNBCEDK-KRWDZBQOSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Displacement of radiolabeled T0901317 from LXRbeta LBD (unknown origin)
Measurement: Ki = 3 nM (pChEMBL 8.520000457763672)
Descriptors: MW 488.53, ALogP 2.23, HBA 8, HBD 2, PSA 106.86, QED 0.64
Compound (SMILES): CS(=O)(=O)c1cc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)ccc1CO
InChIKey: NLDOCDWHNYIGKV-UHFFFAOYSA-N
Target: Oxysterols receptor LXR-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q13133
Assay: Agonist activity at human LXRalpha ligand binding domain(167 to 447 residues) transfected in HEK293 cells after 16 hrs by Gal4-luciferase reporter gene assay
Measurement: EC50 = 205 nM (pChEMBL 6.690000057220459)
Descriptors: MW 595.69, ALogP 5.72, HBA 6, HBD 1, PSA 91.75, QED 0.27
Compound (SMILES): O=c1c(OCCN2CCn3c2nc2ccccc23)cn(CC2CC2)nc1-c1ccnn1-c1ccccc1
InChIKey: PMQGNBOUOYQTPQ-UHFFFAOYSA-N
Target: 3',5'-cyclic-AMP phosphodiesterase 4D (SINGLE PROTEIN), Homo sapiens
UniProt: Q08499
Assay: Inhibition of human PDE4D2
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 493.57, ALogP 3.75, HBA 9, HBD 0, PSA 83, QED 0.33
Compound (SMILES): N[C@@H](COP(=O)(O)O[C@@H]1CCCO[C@@H]1COC(=O)CCc1ccccc1OCc1cccc(Oc2ccccc2)c1)C(=O)O
InChIKey: BIGHQMOUQYMHQN-WIIGKZCBSA-N
Target: Probable G-protein coupled receptor 34 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UPC5
Assay: Agonist activity at human GPR34 expressed in HEK293 cells co-transfected with AP-TGFalpha/chimeric Galphaq/i1 assessed as induction of AP-TGFalpha release after 1 hr
Measurement: EC50 = 150 nM (pChEMBL 6.820000171661377)
Descriptors: MW 629.6, ALogP 4.63, HBA 10, HBD 3, PSA 173.07, QED 0.15
Compound (SMILES): CC1(C)OCCn2c1nc1c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
InChIKey: LGWACEZVCMBSKW-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase mTOR (SINGLE PROTEIN), Homo sapiens
UniProt: P42345
Assay: Inhibition of mTOR (unknown origin)
Measurement: IC50 = 70 nM (pChEMBL 7.159999847412109)
Descriptors: MW 382.43, ALogP 0.97, HBA 10, HBD 1, PSA 117.1, QED 0.69
Compound (SMILES): FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)cn1
InChIKey: JGWRKYUXBBNENE-UHFFFAOYSA-N
Target: Acyl-CoA dehydrogenase family member 11 (SINGLE PROTEIN), Homo sapiens
UniProt: Q709F0
Assay: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
Measurement: Kd > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 417.82, ALogP 5.23, HBA 4, HBD 2, PSA 66.49, QED 0.47
Compound (SMILES): CN(C)CCCn1cc(-c2ccc3c(c2)-c2[nH]c4cc(-c5cn[nH]c5)ccc4c2C3=O)cn1
InChIKey: JRJKATLTRNXYCE-UHFFFAOYSA-N
Target: Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform (SINGLE PROTEIN), Homo sapiens
UniProt: Q16816
Assay: Inhibition of PHKGI (unknown origin) by kinomescan analysis
Measurement: IC50 = 78 nM (pChEMBL 7.110000133514404)
Descriptors: MW 436.52, ALogP 4.58, HBA 5, HBD 2, PSA 82.6, QED 0.4
Compound (SMILES): C[C@@H]1CC(=O)Nc2cccc(-c3ccc4c(c3)c(-c3cnn(C)c3)nn4C)c2N1
InChIKey: BFTKDWYIRJGJCA-CYBMUJFWSA-N
Target: CREB-binding protein (SINGLE PROTEIN), Homo sapiens
UniProt: Q92793
Assay: Displacement of biotinylated ligand from recombinant His-tagged CBP (unknown origin) incubated for 10 mins by TR-FRET assay
Measurement: IC50 = 30 nM (pChEMBL 7.519999980926514)
Descriptors: MW 386.46, ALogP 3.78, HBA 6, HBD 2, PSA 76.77, QED 0.55
Compound (SMILES): COC(=O)c1cc2cc(NCc3cc(NC(=O)c4cc(-n5cnc(C)c5)cc(C(F)(F)F)c4)ccc3C)cnc2[nH]1
InChIKey: PGQWALGGBUYLQF-UHFFFAOYSA-N
Target: Tyrosine-protein kinase ABL1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00519
Assay: Inhibition of His-tagged full length human recombinant ABL G250E mutant expressed in baculovirus using Fluorescein-Poly GT as substrate
Measurement: IC50 = 46 nM (pChEMBL 7.340000152587891)
Descriptors: MW 562.55, ALogP 6.04, HBA 7, HBD 3, PSA 113.93, QED 0.21
Compound (SMILES): CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)c(C(=O)NCc3nccc4ccccc34)c2)NC(=O)N1
InChIKey: UGYAZGXSMRGKRD-UHFFFAOYSA-N
Target: Rho-associated protein kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13464
Assay: Assays for Inhibition of ROCK: Rho-associated coiled-coil kinase (ROCK) assays were performed with the ADP-Glo system using 0.1 μg ROCK1 and 1 μg S6K substrate, and 100 μM ATP for 60 min prior to addition of ADP-GLO Reagent, and allowed to incubate for an additional 40 min prior to the addition of the Kinase Detection Reagent and imaging on a PHERASTAR system.
Measurement: IC50 = 17 nM (pChEMBL 7.769999980926514)
Descriptors: MW 549.57, ALogP 4.45, HBA 5, HBD 5, PSA 140.9, QED 0.21
Compound (SMILES): COc1cccc(OC)c1CNC(=O)c1cc(C2NC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]ncc3c2)ccc1F
InChIKey: KQJWWWZXJNOLQF-UHFFFAOYSA-N
Target: Rho-associated protein kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13464
Assay: Assays for Inhibition of ROCK: Rho-associated coiled-coil kinase (ROCK) assays were performed with the ADP-Glo system using 0.1 μg ROCK1 and 1 μg S6K substrate, and 100 μM ATP for 60 min prior to addition of ADP-GLO Reagent, and allowed to incubate for an additional 40 min prior to the addition of the Kinase Detection Reagent and imaging on a PHERASTAR system.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 558.57, ALogP 3.92, HBA 6, HBD 5, PSA 146.47, QED 0.22
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
InChIKey: WSTCEYSBWKYEDE-UHFFFAOYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay
Measurement: Ki = 0.44 nM (pChEMBL 9.359999656677246)
Descriptors: MW 417.52, ALogP 4.64, HBA 8, HBD 2, PSA 89.78, QED 0.47
Compound (SMILES): COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(N[C@@H](C)C(C)(C)C)c2n1
InChIKey: XTJZKALDRPVFSN-HNNXBMFYSA-N
Target: Dual specificity protein kinase TTK (SINGLE PROTEIN), Homo sapiens
UniProt: P33981
Assay: Inhibition of human full length MPS1 expressed in recombinant baculovirus infected Sf9 insect cells using 5FAM-DHTGFLTEYVATRCONH2 as substrate after 60 to 90 mins in presence of 1 mM ATP
Measurement: Ki = 0.2 nM (pChEMBL 9.699999809265137)
Descriptors: MW 431.54, ALogP 5.02, HBA 8, HBD 2, PSA 89.78, QED 0.44