lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): COc1cc(N[C@H](C(=O)c2c[nH]c3ccc(OC(F)(F)F)cc23)c2ccc(Cl)cc2OC)cc(S(C)(=O)=O)c1
InChIKey: QNOPDDHSGQQLCV-DEOSSOPVSA-N
Target: Cytochrome P450 1A2 (SINGLE PROTEIN), Homo sapiens
UniProt: P05177
Assay: Inhibition of human CYP1A2 preincubated for 5 mins followed by NADPH addition measured after 5 to 30 mins by LC-MS analysis
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 582.98, ALogP 6.18, HBA 7, HBD 2, PSA 106.72, QED 0.23
Compound (SMILES): Cc1nc(NC(=O)N2CCC(C)(C)C2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: NXFPMDWYDKHFMM-UHFFFAOYSA-N
Target: Platelet-derived growth factor receptor alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P16234
Assay: Inhibition of PDGFRalpha (unknown origin)
Measurement: IC50 = 1399.21 nM (pChEMBL 5.849999904632568)
Descriptors: MW 420.47, ALogP 3.77, HBA 7, HBD 1, PSA 102.24, QED 0.69
Compound (SMILES): C=CC(=O)N1C[C@@H](n2nc(C#Cc3c(F)cc4c(ncn4C4CC4)c3F)c(C(N)=O)c2NC)C[C@@H]1COC
InChIKey: YXVDEILMUVTDMK-JKSUJKDBSA-N
Target: Fibroblast growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P21802
Assay: Inhibition of wild type FGFR2 (unknown origin) using 5-FAM-KKKKEEIYFFF-CONH2 peptide as fluorogenic substrate incubated for 80 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay
Measurement: IC50 = 3.7 nM (pChEMBL 8.430000305175781)
Descriptors: MW 523.54, ALogP 2.36, HBA 8, HBD 2, PSA 120.3, QED 0.36
Compound (SMILES): COc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1
InChIKey: CPLSFGHDGOFDRP-UHFFFAOYSA-N
Target: Tyrosine-protein phosphatase non-receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P18031
Assay: Inhibition of full length His-tagged PTP1B (unknown origin) by mobility shift assay
Measurement: IC50 = 1 nM (pChEMBL 9)
Descriptors: MW 326.31, ALogP 0.87, HBA 5, HBD 2, PSA 95.94, QED 0.85
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)O)CC(F)(F)F)cc1OC
InChIKey: XWGKZKKNJOQUSG-SFHVURJKSA-N
Target: Toll-like receptor 8 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR97
Assay: Human TLR8 Assay: TLR8/NF-kB/SEAPorter HEK 293 Cell Line (Imgenex Corporation) is a stably co-transfected cell line which expresses full-length human TLR8 and the secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NF-κB response element. TLR8 expression in this cell line has been tested by flow cytometry. Transfectants with stable expression were selected using the antibiotic blasticidin and geneticin. TLR signaling leads to the translocation of NF-κB and activation of the promoter results in expression of the SEAP gene. TLR8-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37° C. with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the concentration of compound which produced half of the maximal level of SEAP induction for that compound (EC50). TLR8 activity for compounds of the present disclosure was assessed using the human TLR8 assay.
Measurement: EC50 < 10000 nM (pChEMBL 5)
Descriptors: MW 513.56, ALogP 3.38, HBA 8, HBD 4, PSA 133.83, QED 0.3
Compound (SMILES): C=C(C)C(=O)Nc1ccc(-c2c(-c3ccc(Oc4nccc(C)n4)c(F)c3)c3c(N)ncnc3n2C)cc1
InChIKey: XOQVZSSDIQQUGO-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11362
Assay: Inhibition of FGFR1 (unknown origin)
Measurement: IC50 = 864 nM (pChEMBL 6.059999942779541)
Descriptors: MW 509.55, ALogP 5.43, HBA 8, HBD 2, PSA 120.84, QED 0.29
Compound (SMILES): Cc1cc(C)c2c(n1)CN(C(=O)CC1CN(c3ccnc(C(F)(F)F)c3)C1)C2
InChIKey: DTCZNKWBDTXEBS-UHFFFAOYSA-N
Target: Muscarinic acetylcholine receptor M2 (SINGLE PROTEIN), Homo sapiens
UniProt: P08172
Assay: Positive allosteric modulation of human muscarinic M2 receptor expressed in HEK293 cells in presence of EC20 concentration of acetylcholine by Glosensor cAMP assay
Measurement: EC50 = 5700 nM (pChEMBL 5.239999771118164)
Descriptors: MW 390.41, ALogP 3.48, HBA 4, HBD 0, PSA 49.33, QED 0.81
Compound (SMILES): C=CC(=O)Nc1cc(Nc2nccc(Nc3cc(Cl)c(F)cc3C(C)(C)O)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
InChIKey: BTMKEDDEMKKSEF-QGZVFWFLSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR M766_A767Ins ASV mutant in patient-derived human LXF 2478 cells by HTRF assay
Measurement: IC50 = 31.62 nM (pChEMBL 7.5)
Descriptors: MW 584.1, ALogP 5.26, HBA 9, HBD 4, PSA 114.88, QED 0.24
Compound (SMILES): Nc1ncc(-c2ccc([C@@]34C[C@@H]3CN(C3CCOCC3)C4)cc2)cc1C(=O)NC12CCC(O)(CC1)CC2
InChIKey: KPRPFTOLWQQUAV-OCVAFRRMSA-N
Target: Activin receptor type-1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q04771
Assay: Caliper Assay: A kinase selectivity panel which measures substrate peptide phosphorylation was set-up for wild-type ALK2 (aa172-499), ALK2 FOP mutant (aa172-499 R206H), ALK1 (aa166-493), ALK5 (aa162-503) and ALK6 (aa168-495). The technology used for the described assay is based on the separation and quantification of substrate and product in an electrical field. In the course of the kinase reaction the peptide substrate is phosphorylated by a kinase. The transfer of a phosphate residue also causes the introduction of two additional negative charges and hence to a change in the net charge of the phospho-peptide compared to the unphosphorylated peptide. Due to this difference in charge the phosphorylated und unphosphorylated peptides migrate with different velocities in an electrical field.In the applied method, this separation takes place inside a chip that contains a complex capillary system for simultaneous analysis of 12 samples (12-sipper chip, Caliper Technologies Corp., Mountain View, USA). In order to allow the detection and quantification of the peptides in the capillary system, the peptides carry a fluorescent label (fluorescein). With this label the peptides can be quantified by fluorescence intensity through the instruments laser and detection system (LC3000, Caliper Life Sciences).The assays were performed in 384-well, low volume microtiter assay plates in a final reaction volume of 9 ul. Dose-response curves were generated by incubating 10 nM of each kinase together with 2 μm of the fluorescently labeled substrate peptide 5-Fluo-Ahx-KKYQAEEN-T-YDEYENKK-amid (10 mM stock solution in DMSO) in 50 mM Hepes pH 7.5, 0.02% Tween 20, 0.02% BSA, 1 mM DTT, 10 m Na3VO4, 10 mM If-Glycerolphosphate, 1 mM MgCl2, 12 mM MnCl2 (ALK1 and ALK6 7 mM) and 15 μm ATP for 60 min at 30° C. in the presence or absence of compound diluted in DMSO. Kinase reaction were terminated by adding 15 ul STOP buffer (100 mM HEPES pH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA, and 0.015% Brij35.Plates with terminated kinase reactions were transferred to the Caliper LC3000 workstation (Caliper Technologies Corp., Mountain View, USA) for reading. The relative amount of phosphorylated peptide r, was calculated using the heights of the substrate peak, s, and the product peak, p: r=p/(p+s).
Measurement: IC50 = 21 nM (pChEMBL 7.679999828338623)
Descriptors: MW 502.66, ALogP 3.65, HBA 6, HBD 3, PSA 100.71, QED 0.58
Compound (SMILES): CC(C)[C@H](N)C(=O)SCC/C=C/[C@@H]1CC(=O)NCc2nc(cs2)C(=O)NC(C)(C)C(=O)N[C@@H](C(C)C)C(=O)O1.O=S(=O)(O)c1ccccc1
InChIKey: NIRZCQHSBOSBOH-CVYLVPDPSA-N
Target: Histone deacetylase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q92769
Assay: Inhibition of human full length recombinant HDAC2 expressed in baculovirus infected Sf9 cells using RHKKAc as substrate preincubated for 10 mins followed by substrate addition and measured after 2 hrs by fluorescence based analysis
Measurement: IC50 = 2.4 nM (pChEMBL 8.619999885559082)
Descriptors: MW 581.76, ALogP 1.91, HBA 10, HBD 4, PSA 169.58, QED 0.21
Compound (SMILES): C[C@@H](NC(=O)N1C(=O)[C@H](Cc2ccnc(N)c2)[C@H]1C(=O)O)C1CCCCC1
InChIKey: NYPSZHLKEMYZKK-XFJVYGCCSA-N
Target: Prothrombin (SINGLE PROTEIN), Homo sapiens
UniProt: P00734
Assay: Inhibition of human thrombin
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 374.44, ALogP 1.8, HBA 5, HBD 3, PSA 125.62, QED 0.67
Compound (SMILES): CCOCc1cnc(Cl)nc1Oc1ccc2c(ccc3sc4c(c32)NC[C@@H](C)NC4=O)n1
InChIKey: PYOQIOLRFIRRSO-LLVKDONJSA-N
Target: MAP kinase-activated protein kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P49137
Assay: Mass Spectrometry Assay: Compounds I-1 through I-50 of the invention were assayed in a mass spectrometric assay to measure their ability to covalently modify MK2 protein. The procedure for this assay follows. Intact MK2 protein (Invitrogen, Cat. No. PR5320A) was incubated for 60 minutes at room temperature with a 10-fold excess of test compound to protein. Aliquots of the resulting mixture (6 μL each) were diluted with 0.2% trifluoroacetic acid (TFA, 10 μL) prior to micro C4 ZipTipping directly onto the MALDI target using sinapinic acid as the desorption matrix (10 mg/ml in 0.1% TFA:acetonitrile 50:50, v/v). The centroid mass of the target protein in the control sample was compared with the centroid mass of the target protein incubated with compound. A shift in the centroid mass of the treated protein compared to the untreated protein was divided by the molecular weight of the compound. This number corresponds to the percentage of modified protein (a measure of the proportion of total target protein covalently bound to the test compound) after one hour incubation. Results from this assay are reported in Table A under the column ¿Mass Modification¿.
Measurement: IC50 = 300 nM (pChEMBL 6.519999980926514)
Descriptors: MW 469.95, ALogP 4.77, HBA 8, HBD 2, PSA 98.26, QED 0.41
Compound (SMILES): Cn1cc(-c2ccc(CNc3cc(-c4cnc5cc(OCCCN6CCCC6)ccn45)ncn3)cc2)cn1
InChIKey: LVMAULGVWBINFP-UHFFFAOYSA-N
Target: Platelet-derived growth factor receptor alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P16234
Assay: Inhibition of PDGFRA (unknown origin) using 33P-ATP as substrate incubated for 120 mins by radiometric kinase assay
Measurement: IC50 = 50 nM (pChEMBL 7.300000190734863)
Descriptors: MW 508.63, ALogP 4.67, HBA 9, HBD 1, PSA 85.4, QED 0.27
Compound (SMILES): Br.O=C(NO)c1ccc(Cn2cc(CN[C@@H]3C[C@H]3c3ccccc3)cn2)cc1
InChIKey: VYVGGNXALTUECS-CMXBXVFLSA-N
Target: Protein deacetylase HDAC6 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UBN7
Assay: Inhibition of HDAC6 (unknown origin)
Measurement: IC50 = 11 nM (pChEMBL 7.960000038146973)
Descriptors: MW 362.43, ALogP 2.7, HBA 5, HBD 3, PSA 79.18, QED 0.45
Compound (SMILES): Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C)s3)nc(C)n2)nc1
InChIKey: WQKPZDLZRFTMTI-CABCVRRESA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Displacement of MK499 from hERG
Measurement: IC50 = 33000 nM (pChEMBL 4.480000019073486)
Descriptors: MW 382.49, ALogP 3.44, HBA 8, HBD 1, PSA 85.71, QED 0.67
Compound (SMILES): CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)N3CCc4cc(Cn5nc(-c6ccc7oc(N)nc7c6)c6c(N)ncnc65)ccc4C3)[C@H](OC)C2)C[C@@H](O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
InChIKey: IUTYTXDIGUNPAA-GKVGALOGSA-N
Target: mTORC1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9BVC4
Assay: Inhibition of mTORC1 in human MDA-MB-468 cells assessed as reduction in 4EBP1 phosphorylation at Thr37/46 by AlphaLISA assay
Measurement: IC50 = 1.6 nM (pChEMBL 8.800000190734863)
Descriptors: MW 1778.16
Compound (SMILES): Cn1cncc1-c1c(F)cncc1NC(=O)c1c(N)nn2cc(F)cnc12
InChIKey: RBQPCTBFIPVIJN-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition Assay: Compounds were screened for their ability to inhibit ATR kinase using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgCl2 and 1 mM DTT. Final substrate concentrations were 10 μM [γ-33P]ATP (3mCi 33P ATP/mmol ATP, Perkin Elmer) and 800 μM target peptide (ASELPASQPQPFSAKKK) (SEQ ID NO:1).Assays were carried out at 25° C. in the presence of 5 nM full-length ATR. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 13.5 μL of the stock solution was placed in a 96 well plate followed by addition of 2 μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 μM with 3-fold serial dilutions) in duplicate (final DMSO concentration 7%). The plate was pre-incubated for 10 minutes at 25° C. and the reaction initiated by addition of 15 μL [γ-33P]ATP (final concentration 10 μM).The reaction was stopped after 24 hours by the addition of 30 μL 0.1M phosphoric acid containing 2 mM ATP. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with 100 μL 0.2M phosphoric acid prior to the addition of 454 of the stopped assay mixture. The plate was washed with 5×200 μL 0.2M phosphoric acid. After drying, 100 μL Optiphase SuperMix liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
Measurement: Ki < 10 nM (pChEMBL 8)
Descriptors: MW 370.32, ALogP 1.64, HBA 8, HBD 2, PSA 116.02, QED 0.57
Compound (SMILES): C[C@@H](O)[C@@H](C(N)=O)N1C[C@@]2(CCCN2C(=O)OC(C)(C)C)C1=O
InChIKey: ABAPCYNTEPGBNJ-FTGAXOIBSA-N
Target: Glutamate receptor ionotropic, NMDA 2C (SINGLE PROTEIN), Homo sapiens
UniProt: Q14957
Assay: Positive allosteric modulation of human GluN2C receptor expressed in HEK293 cells by Whole-cell patch-clamp method
Measurement: EC50 = 9700 nM (pChEMBL 5.010000228881836)
Descriptors: MW 327.38, ALogP -0.17, HBA 5, HBD 2, PSA 113.17, QED 0.7
Compound (SMILES): Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1.O.O
InChIKey: FPKARFMSZDBYQF-ILKKLZGPSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Compound was evaluated for inhibition of human KCNH2 in an in vitro assay with cellular components measured by membrane filtration, radioactivity method
Measurement: AC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 279.19, ALogP -1.66, HBA 7, HBD 4, PSA 147.9, QED 0.45
Compound (SMILES): CC[C@H]1[C@@H]2C[C@H]3[C@@H]4N(C)c5ccccc5[C@]45C[C@@H]([C@@H]2[C@H]5O)N3[C@@H]1O
InChIKey: CJDRUOGAGYHKKD-OVXZWHIBSA-N
Target: Voltage-dependent L-type calcium channel subunit alpha-1C (SINGLE PROTEIN), Rattus norvegicus
UniProt: P22002
Assay: Inhibition of L-type calcium channel measured using whole-cell patch clamp in rat ventricular myocytes
Measurement: IC50 = 70800 nM (pChEMBL 4.150000095367432)
Descriptors: MW 326.44, ALogP 1.55, HBA 4, HBD 2, PSA 46.94, QED 0.82
Compound (SMILES): CNC(=O)c1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccnc2cc1OC
InChIKey: JSPCKALGNNVYOO-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Mer (SINGLE PROTEIN), Homo sapiens
UniProt: Q12866
Assay: Mer Kinase Assay: Human Mer (residues R557-E882 with H628Q and R794A, 0.7 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 30 mM NaCl, 250 μM GGMEDIYFEFMGGKKK (SEO ID NO. 44). 10 mM magnesium acetate, and 10 μM [γ-33P-ATP]. The reaction was initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%. A reaction aliquot of 10 μL was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting. Incorporated 33P was measured using the Wallac Microbeta scintillation counter (Perkin Elmer).
Measurement: IC50 < 10 nM (pChEMBL 8)
Descriptors: MW 528.54, ALogP 4.89, HBA 6, HBD 3, PSA 118.65, QED 0.28
Compound (SMILES): COc1cc2nccc(Oc3ccc(NC(=O)c4cc5c(n(-c6ccccc6)c4=O)CCCC5=O)nc3)c2cc1OC
InChIKey: WHMMKPWGWNYYFE-UHFFFAOYSA-N
Target: Tyrosine-protein kinase receptor UFO (SINGLE PROTEIN), Homo sapiens
UniProt: P30530
Assay: Inhibition of AXL (unknown origin) preincubated for 15 mins followed by substrate and ATP addition and measured after 3 hrs by ADP-Glo kinase assay
Measurement: IC50 = 2.2 nM (pChEMBL 8.65999984741211)
Descriptors: MW 562.58, ALogP 5.36, HBA 9, HBD 1, PSA 121.64, QED 0.28
Compound (SMILES): C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@](COc7ncccc7C#N)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
InChIKey: PQBROJOHKLMPKM-WJGXRGGQSA-N
Target: Cytochrome P450 2C8 (SINGLE PROTEIN), Homo sapiens
UniProt: P10632
Assay: Inhibition of CYP2C8 (unknown origin)
Measurement: IC50 > 4400 nM (pChEMBL 5.35699987411499)
Descriptors: MW 827.19, ALogP 8.78, HBA 8, HBD 2, PSA 132.62, QED 0.22
Compound (SMILES): NC(=O)c1c(N)nn2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)ccc3F)nc12
InChIKey: YFTARXQOKASKBW-JOYOIKCWSA-N
Target: NT-3 growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: Q16288
Assay: Inhibitory Activity Assay: TrkA, TrkB and TrkC:A testing platform for TrkA, TrkB and TrkC kinase activity was established based on Homogeneous Time-Resolved Fluorescence (HTRF) assay, and the activities of the compounds were tested using the platform. The compounds were subjected to three-fold gradient dilution with 100% DMSO with a starting concentration of 1 mM (11 concentrations in total). 4 μL of diluted sample for each concentration was added to 96 μL of reaction buffer (50 mM HEPES, pH7.4, 5 mM MgCl2, 1 mM NaVO3, 0.001% Tween-20, 0.01% BSA and 1 mM DTT) and mixed homogeneously to be used as a 4* compound. The reaction buffer was used to formulate 2* TrkA, TrkB and TrkC kinases (purchased from Carna Biosciences 08-186, 08-187, 08-197, and the final concentrations thereof were 0.5 nM, 0.1 nM, and 1 nM, respectively) and 4* substrate mixture (ATP+TK peptide) (wherein the final concentrations of ATP were 40 μM, 50 μM, and 20 μM, respectively; TK peptide, HTRF® KinEASE-TK, was purchased from Cisbio, and the final concentration thereof was 100 nM) for use. 2.5 μL of the 4* compound was added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and then 5 μL of the 2* TrkA, TrkB and TrkC kinases were added, and mixed homogeneously by centrifugation. Then 2.5 μL of the 4* substrate mixture was added to initiate the reaction (the total reaction volume is 10 μL). The 384-well plate was placed in an incubator and incubated for 60 min at 23° C. Then the reaction was terminated by adding 5 μL of Eu3+ cryptate-labeled anti-phosphotyrosine antibody (HTRF® KinEASE-TK, purchased from Cisbio), and 5 μL of Streptavidin-XL-665 (HTRF® KinEASE-TK, purchased from Cisbio). After incubated for 1 hr in the incubator, the fluorescence values were read on Envision (purchased from PerkinElmer).
Measurement: IC50 < 1 nM (pChEMBL 9)
Descriptors: MW 376.34, ALogP 1.98, HBA 6, HBD 2, PSA 102.54, QED 0.73
Compound (SMILES): Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cncc(-c3oncc3C)c2)n1
InChIKey: ADGOPPKEIZXKAZ-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Kinase Assay: Kinase base buffer (50 mM HEPES, pH 7.5 0.0015% Brij-35; 10 mM MgCl2 2 mM DTT) and Stop buffer, (100 mM HEPES, pH 7.5 0.015% Brij-35; 0.2% Coating Reagent (50 mM EDTA) are prepared. Test compound is diluted in 100% DMSO to 50-times the desired final inhibitor concentration (the Stock Solution) and serially diluted in half-log increments resulting in final concentrations 250 μM to 75 μM, 25 μM, 7.5 μM, 2.5 μM, 0.75 μM, 0.25 μM, 75 nM, 25 nM, 7.5 nM in DMSO. 10 μl of each compound is placed in a 96-well plate as the intermediate plate. 90 μl of Kinase Buffer is added to to each well to prepare the intermediate plate.Figure US10906896-20210202-P00001Mix the compounds in intermediate plate for 10 min on shaker. For the assay of enzyme inhibitions, 5 μl of each well from the intermediate plate is transferred to a 384-well plate in duplicates, 10. Then 10 μl of 2.5× enzyme solution is added to each well of the 384-well assay plate and incubated for 10 min. Then enzyme substrate is added as 10 μl of 2.5×FAM-labeled peptide+ATP solution to each well of the 384-well assay plate. The reaction is allowed to proceed at 28° C. and quenched with the addition of 25 μl of stop buffer.
Measurement: Ki = 7.8 nM (pChEMBL 8.109999656677246)
Descriptors: MW 574.69, ALogP 5.55, HBA 9, HBD 2, PSA 112.31, QED 0.25
Compound (SMILES): CC(C)c1ccc(N(C)c2ccc3c(c2)OCC[C@H]3CNc2cnccc2C(=O)O)cc1
InChIKey: NDVITLLKZQXKGU-IBGZPJMESA-N
Target: Lysine-specific demethylase 4A (SINGLE PROTEIN), Homo sapiens
UniProt: O75164
Assay: Inhibition of KDM4A (unknown origin)
Measurement: IC50 = 80 nM (pChEMBL 7.099999904632568)
Descriptors: MW 431.54, ALogP 5.65, HBA 5, HBD 2, PSA 74.69, QED 0.5
Compound (SMILES): C[C@H]1CN2CCNCc3ccc(C(=O)NCC(F)F)c1c32
InChIKey: KGOOOHQKLRUVSF-VIFPVBQESA-N
Target: 5-hydroxytryptamine receptor 2B (SINGLE PROTEIN), Homo sapiens
UniProt: P41595
Assay: Displacement of [125I]-DOI from 5-HT2B receptor (unknown origin) expressed in HEK293 cell membrane assessed as inhibition constant incubated for 1 hr by scintillation counter analysis
Measurement: Ki > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 295.33, ALogP 1.71, HBA 3, HBD 2, PSA 44.37, QED 0.89
Compound (SMILES): C=CC(=O)N1CCN(c2c(C#N)c(=O)n(-c3c(C)ccnc3C(C)C)c3nc(-c4c(N)c(F)c(F)c(F)c4F)c(Cl)cc23)CC1
InChIKey: QRRJEUIQLZNPIO-UHFFFAOYSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of human ERG
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 640.04, ALogP 5.38, HBA 8, HBD 1, PSA 121.14, QED 0.1
Compound (SMILES): COc1cc(N[C@H](C(=O)c2c[nH]c3ccc(OC(F)(F)F)cc23)c2ccc(Cl)cc2OC)cc(S(C)(=O)=O)c1
InChIKey: QNOPDDHSGQQLCV-DEOSSOPVSA-N
Target: Cytochrome P450 2C8 (SINGLE PROTEIN), Homo sapiens
UniProt: P10632
Assay: Inhibition of human CYP2C8 preincubated for 5 mins followed by NADPH addition measured after 5 to 30 mins by LC-MS analysis
Measurement: IC50 = 7400 nM (pChEMBL 5.130000114440918)
Descriptors: MW 582.98, ALogP 6.18, HBA 7, HBD 2, PSA 106.72, QED 0.23
Compound (SMILES): Cc1nc(NC(=O)N2CCC(C)(C)C2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
InChIKey: NXFPMDWYDKHFMM-UHFFFAOYSA-N
Target: Macrophage colony-stimulating factor 1 receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P07333
Assay: Inhibition of CSF1R (unknown origin) using ATP as substrate incubated for 1 hr by Z-LYTE based FRET assay
Measurement: IC50 = 19.48 nM (pChEMBL 7.710000038146973)
Descriptors: MW 420.47, ALogP 3.77, HBA 7, HBD 1, PSA 102.24, QED 0.69
Compound (SMILES): C=CC(=O)N1C[C@@H](n2nc(C#Cc3c(F)cc4c(ncn4C4CC4)c3F)c(C(N)=O)c2NC)C[C@@H]1COC
InChIKey: YXVDEILMUVTDMK-JKSUJKDBSA-N
Target: Fibroblast growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P21802
Assay: Inhibition of FGFR2 N549H mutant (unknown origin) using 5-FAM-KKKKEEIYFFF-CONH2 peptide as fluorogenic substrate incubated for 80 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay
Measurement: IC50 = 23.3 nM (pChEMBL 7.630000114440918)
Descriptors: MW 523.54, ALogP 2.36, HBA 8, HBD 2, PSA 120.3, QED 0.36
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)O)CC(F)(F)F)cc1OC
InChIKey: XWGKZKKNJOQUSG-SFHVURJKSA-N
Target: Toll-like receptor 7 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NYK1
Assay: Human TLR7 Assay: Recombinant human TLR7 was stably expressed in a HEK293 cell line already stably expressing the pNiFty2-SEAP reporter plasmid; integration of the reporter gene was maintained by selection with the antibiotic zeocin. The most common variant sequence of human TLR7 (represented by the EMBL sequence AF240467) was cloned into the mammalian cell expression vector pUNO and transfected into this reporter cell-line. Transfectants with stable expression were selected using the antibiotic blasticidin. In this reporter cell-line, expression of secreted alkaline phosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promoter comprising five NFkB sites combined with the proximal ELAM-1 promoter. TLR signaling leads to the translocation of NFkB and activation of the promoter results in expression of the SEAP gene. TLR7-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37° C. with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the concentration of compound which produced half of the maximal level of SEAP induction for that compound (EC50).
Measurement: EC50 = 100 nM (pChEMBL 7)
Descriptors: MW 513.56, ALogP 3.38, HBA 8, HBD 4, PSA 133.83, QED 0.3
Compound (SMILES): C=C(C)C(=O)Nc1ccc(-c2c(-c3ccc(Oc4nccc(C)n4)c(F)c3)c3c(N)ncnc3n2C)cc1
InChIKey: XOQVZSSDIQQUGO-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P22607
Assay: Inhibition of FGFR3 (unknown origin)
Measurement: IC50 = 274 nM (pChEMBL 6.559999942779541)
Descriptors: MW 509.55, ALogP 5.43, HBA 8, HBD 2, PSA 120.84, QED 0.29
Compound (SMILES): Cc1cc(C)c2c(n1)CN(C(=O)CC1CN(c3ccnc(C(F)(F)F)c3)C1)C2
InChIKey: DTCZNKWBDTXEBS-UHFFFAOYSA-N
Target: Muscarinic acetylcholine receptor M4 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P08485
Assay: Positive allosteric modulation of rat muscarinic M4 receptor expressed in HEK293 cells in presence of EC20 concentration of acetylcholine by Glosensor cAMP assay
Measurement: EC50 = 80 nM (pChEMBL 7.099999904632568)
Descriptors: MW 390.41, ALogP 3.48, HBA 4, HBD 0, PSA 49.33, QED 0.81
Compound (SMILES): C=CC(=O)Nc1cc(Nc2nccc(Nc3cc(Cl)c(F)cc3C(C)(C)O)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
InChIKey: BTMKEDDEMKKSEF-QGZVFWFLSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR D770_N771insNPG mutant (unknown origin) by HTRF assay
Measurement: IC50 = 25.12 nM (pChEMBL 7.599999904632568)
Descriptors: MW 584.1, ALogP 5.26, HBA 9, HBD 4, PSA 114.88, QED 0.24
Compound (SMILES): Nc1ncc(-c2ccc([C@@]34C[C@@H]3CN(C3CCOCC3)C4)cc2)cc1C(=O)NC12CCC(O)(CC1)CC2
InChIKey: KPRPFTOLWQQUAV-OCVAFRRMSA-N
Target: TGF-beta receptor type-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P36897
Assay: Caliper Assay: A kinase selectivity panel which measures substrate peptide phosphorylation was set-up for wild-type ALK2 (aa172-499), ALK2 FOP mutant (aa172-499 R206H), ALK1 (aa166-493), ALK5 (aa162-503) and ALK6 (aa168-495). The technology used for the described assay is based on the separation and quantification of substrate and product in an electrical field. In the course of the kinase reaction the peptide substrate is phosphorylated by a kinase. The transfer of a phosphate residue also causes the introduction of two additional negative charges and hence to a change in the net charge of the phospho-peptide compared to the unphosphorylated peptide. Due to this difference in charge the phosphorylated und unphosphorylated peptides migrate with different velocities in an electrical field.In the applied method, this separation takes place inside a chip that contains a complex capillary system for simultaneous analysis of 12 samples (12-sipper chip, Caliper Technologies Corp., Mountain View, USA). In order to allow the detection and quantification of the peptides in the capillary system, the peptides carry a fluorescent label (fluorescein). With this label the peptides can be quantified by fluorescence intensity through the instruments laser and detection system (LC3000, Caliper Life Sciences).The assays were performed in 384-well, low volume microtiter assay plates in a final reaction volume of 9 ul. Dose-response curves were generated by incubating 10 nM of each kinase together with 2 μm of the fluorescently labeled substrate peptide 5-Fluo-Ahx-KKYQAEEN-T-YDEYENKK-amid (10 mM stock solution in DMSO) in 50 mM Hepes pH 7.5, 0.02% Tween 20, 0.02% BSA, 1 mM DTT, 10 m Na3VO4, 10 mM If-Glycerolphosphate, 1 mM MgCl2, 12 mM MnCl2 (ALK1 and ALK6 7 mM) and 15 μm ATP for 60 min at 30° C. in the presence or absence of compound diluted in DMSO. Kinase reaction were terminated by adding 15 ul STOP buffer (100 mM HEPES pH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA, and 0.015% Brij35.Plates with terminated kinase reactions were transferred to the Caliper LC3000 workstation (Caliper Technologies Corp., Mountain View, USA) for reading. The relative amount of phosphorylated peptide r, was calculated using the heights of the substrate peak, s, and the product peak, p: r=p/(p+s).
Measurement: IC50 = 6280 nM (pChEMBL 5.199999809265137)
Descriptors: MW 502.66, ALogP 3.65, HBA 6, HBD 3, PSA 100.71, QED 0.58
Compound (SMILES): CC(C)[C@H](N)C(=O)SCC/C=C/[C@@H]1CC(=O)NCc2nc(cs2)C(=O)NC(C)(C)C(=O)N[C@@H](C(C)C)C(=O)O1.O=S(=O)(O)c1ccccc1
InChIKey: NIRZCQHSBOSBOH-CVYLVPDPSA-N
Target: Histone deacetylase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O15379
Assay: Inhibition of recombinant full length human HDAC3 expressed in insect Sf9 cells
Measurement: IC50 = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 581.76, ALogP 1.91, HBA 10, HBD 4, PSA 169.58, QED 0.21
Compound (SMILES): Cn1cc(-c2ccc(CNc3cc(-c4cnc5cc(OCCCN6CCCC6)ccn45)ncn3)cc2)cn1
InChIKey: LVMAULGVWBINFP-UHFFFAOYSA-N
Target: Platelet-derived growth factor receptor beta (SINGLE PROTEIN), Homo sapiens
UniProt: P09619
Assay: Inhibition of PDGFRB (unknown origin) using 33P-ATP as substrate incubated for 120 mins by radiometric kinase assay
Measurement: IC50 = 2.6 nM (pChEMBL 8.59000015258789)
Descriptors: MW 508.63, ALogP 4.67, HBA 9, HBD 1, PSA 85.4, QED 0.27
Compound (SMILES): Br.O=C(NO)c1ccc(Cn2cc(CN[C@@H]3C[C@H]3c3ccccc3)cn2)cc1
InChIKey: VYVGGNXALTUECS-CMXBXVFLSA-N
Target: Histone deacetylase 8 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9BY41
Assay: Inhibition of HDAC8 (unknown origin)
Measurement: IC50 = 98 nM (pChEMBL 7.010000228881836)
Descriptors: MW 362.43, ALogP 2.7, HBA 5, HBD 3, PSA 79.18, QED 0.45
Compound (SMILES): Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C)s3)nc(C)n2)nc1
InChIKey: WQKPZDLZRFTMTI-CABCVRRESA-N
Target: Nuclear receptor subfamily 1 group I member 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75469
Assay: Activation of PXR (unknown origin) assessed as CYP3A4 induction
Measurement: EC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 382.49, ALogP 3.44, HBA 8, HBD 1, PSA 85.71, QED 0.67
Compound (SMILES): Cn1cncc1-c1c(F)cncc1NC(=O)c1c(N)nn2cc(F)cnc12
InChIKey: RBQPCTBFIPVIJN-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition Assay: Table 5: Compounds were screened for their ability to inhibit ATR kinase using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgCl2 and 1 mM DTT. Final substrate concentrations were 10 μM [y-33P]ATP (3 mCi 33P ATP/mmol ATP, Perkin Elmer) and 800 μM target peptide(ASELPASQPQPFSAKKK) (SEQ ID NO:1).Assays were carried out at 25° C. in the presence of 5 nM full-length ATR. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 13.5 μL of the stock solution was placed in a 96 well plate followed by addition of 2 μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 μM with 3-fold serial dilutions) in duplicate (final DMSO concentration 7%). The plate was pre-incubated for 10 minutes at 25° C. and the reaction initiated by addition of 15 μL [γ-33P]ATP (final concentration 10 μM).
Measurement: Ki = 550 nM (pChEMBL 6.260000228881836)
Descriptors: MW 370.32, ALogP 1.64, HBA 8, HBD 2, PSA 116.02, QED 0.57
Compound (SMILES): Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1.O.O
InChIKey: FPKARFMSZDBYQF-ILKKLZGPSA-N
Target: Sodium-dependent dopamine transporter (SINGLE PROTEIN), Homo sapiens
UniProt: Q01959
Assay: Binding affinity towards human SLC6A3 in an in vitro assay with cellular components measured by scintillation counting
Measurement: AC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 279.19, ALogP -1.66, HBA 7, HBD 4, PSA 147.9, QED 0.45
Compound (SMILES): COc1cc2ncc3c(c2cc1-c1cn(C)nc1C)n(-c1c(F)cncc1OC)c(=O)n3C
InChIKey: WNEFOSMCGCLLJU-UHFFFAOYSA-N
Target: PI3-kinase p110-alpha/p85-alpha (PROTEIN COMPLEX), Homo sapiens
UniProt: P42336
Assay: PI3K p110alpha/p85alpha (Human), Non-radioactive Assay: PI3K p110α/p85α (human) was incubated in an assay buffer comprising 10 μM phosphati-dylinositol 4,5-bisphosphate and MgATP (concentration as necessary). The reaction was initiated by addition of MgATP solution. After incubation at room temperature for 40 minutes, the reaction was stopped by addition of a solution consisting of EDTA and biotinylated phosphatidylinositol 3,4,5-trisphosphate. Finally, the detection buffer, consisting of a europium-labelled anti-GST monoclonal antibody, a GST-labelled GRP1 PH domain and streptavidin allophycocyanin, was added. The plate was read out via homogeneous time-resolved fluorescence (HTRF) and the corresponding signals were evaluated via the formula HTRF=10000×(Em665nm/Em620nm).
Measurement: IC50 > 5000 nM (pChEMBL 5.301000118255615)
Descriptors: MW 448.46, ALogP 3.14, HBA 9, HBD 0, PSA 88.99, QED 0.42
Compound (SMILES): CNC(=O)c1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccnc2cc1OC
InChIKey: JSPCKALGNNVYOO-UHFFFAOYSA-N
Target: Hepatocyte growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P08581
Assay: Met Kinase Assay: Human Met (residues R974-S1390 with A1209G and V1290L, 3.4 nM) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKKGQEEEYVFIE (SEO ID NO. 45), 1 mM sodium orthovanadate, 5 mM sodium-6-glycerophosphate, 10 mM magnesium acetate, and 10 μM [γ-33P-ATP]. The reaction was initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%. A reaction aliquot of 10 sL was then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting. Incorporated 33P was measured using the Wallac Microbeta scintillation counter (Perkin Elmer).
Measurement: IC50 < 10 nM (pChEMBL 8)
Descriptors: MW 528.54, ALogP 4.89, HBA 6, HBD 3, PSA 118.65, QED 0.28
Compound (SMILES): C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@](COc7ncccc7C#N)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
InChIKey: PQBROJOHKLMPKM-WJGXRGGQSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 (unknown origin)
Measurement: IC50 > 4400 nM (pChEMBL 5.35699987411499)
Descriptors: MW 827.19, ALogP 8.78, HBA 8, HBD 2, PSA 132.62, QED 0.22
Compound (SMILES): NC(=O)c1c(N)nn2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)ccc3F)nc12
InChIKey: YFTARXQOKASKBW-JOYOIKCWSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Homogeneous Time-Resolved Fluorescence (HTRF) Assay: JAK2: A testing platform for JAK2 kinase activity was established based on Homogeneous Time-Resolved Fluorescence (HTRF) assay, and the activities of the compounds were tested using the platform. The compounds were subjected to three-fold gradient dilution with 100% DMSO with a starting concentration of 1 mM (11 concentrations in total). 4 μL of diluted sample for each concentration was added to 96 μL of reaction buffer (50 mM HEPES, pH7.4, 10 mM MgCl2, 1 mM EDTA, 0.01% Tween-20, 0.005% BSA and 2 mM DTT) and mixed homogeneously. 2.5 μL of the resulting liquid was then added to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), and 5 μL of JAK2 kinase (purchased from Carna, and the final concentration thereof is 0.05 nM) was added, and mixed homogeneously by centrifugation. Then 2.5 μL of a mixture of ATP (the final concentration is 5 μM) and TK peptide (HTRF® KinEASE-TK, purchased from Cisbio, and the final concentration is 100 nM) was added to initiate the reaction (the total reaction volume is 10 μL). The 384-well plate was placed in an incubator to incubate for 120 min at 23° C. Then the reaction was terminated by adding 5 μL of Eu3+ cryptate-labled anti-phosphotyrosine antibody (purchased from Cisbio), and 5 μL of Streptavidin-XL-665 (HTRF® KinEASE-TK, purchased from Cisbio). After incubated for 1 hr in the incubator, the fluorescence values were read on Envision (purchased from PerkinElmer).
Measurement: IC50 > 100 nM (pChEMBL 7)
Descriptors: MW 376.34, ALogP 1.98, HBA 6, HBD 2, PSA 102.54, QED 0.73
Compound (SMILES): CC(C)c1ccc(N(C)c2ccc3c(c2)OCC[C@H]3CNc2cnccc2C(=O)O)cc1
InChIKey: NDVITLLKZQXKGU-IBGZPJMESA-N
Target: Lysine-specific demethylase 4B (SINGLE PROTEIN), Homo sapiens
UniProt: O94953
Assay: Inhibition of KDM4B (unknown origin)
Measurement: IC50 = 58 nM (pChEMBL 7.239999771118164)
Descriptors: MW 431.54, ALogP 5.65, HBA 5, HBD 2, PSA 74.69, QED 0.5
Compound (SMILES): C[C@H]1CN2CCNCc3ccc(C(=O)NCC(F)F)c1c32
InChIKey: KGOOOHQKLRUVSF-VIFPVBQESA-N
Target: 5-hydroxytryptamine receptor 2A (SINGLE PROTEIN), Homo sapiens
UniProt: P28223
Assay: Displacement of [125I]-DOI from 5-HT2A receptor (unknown origin) expressed in HEK293 cell membrane assessed as inhibition constant incubated for 1 hr by scintillation counter analysis
Measurement: Ki > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 295.33, ALogP 1.71, HBA 3, HBD 2, PSA 44.37, QED 0.89
Compound (SMILES): C=CC(=O)N1CCN(c2c(C#N)c(=O)n(-c3c(C)ccnc3C(C)C)c3nc(-c4c(N)c(F)c(F)c(F)c4F)c(Cl)cc23)CC1
InChIKey: QRRJEUIQLZNPIO-UHFFFAOYSA-N
Target: UDP-glucuronosyltransferase 1A1 (SINGLE PROTEIN), Homo sapiens
UniProt: P22309
Assay: Inhibition of UGT1A1 (unknown origin)
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 640.04, ALogP 5.38, HBA 8, HBD 1, PSA 121.14, QED 0.1
Compound (SMILES): COc1cc(N[C@H](C(=O)c2c[nH]c3ccc(OC(F)(F)F)cc23)c2ccc(Cl)cc2OC)cc(S(C)(=O)=O)c1
InChIKey: QNOPDDHSGQQLCV-DEOSSOPVSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of human CYP2C9 preincubated for 5 mins followed by NADPH addition measured after 5 to 30 mins by LC-MS analysis
Measurement: IC50 = 3700 nM (pChEMBL 5.429999828338623)
Descriptors: MW 582.98, ALogP 6.18, HBA 7, HBD 2, PSA 106.72, QED 0.23
Compound (SMILES): C=CC(=O)N1C[C@@H](n2nc(C#Cc3c(F)cc4c(ncn4C4CC4)c3F)c(C(N)=O)c2NC)C[C@@H]1COC
InChIKey: YXVDEILMUVTDMK-JKSUJKDBSA-N
Target: Fibroblast growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P21802
Assay: Inhibition of FGFR2 V564F mutant (unknown origin) using 5-FAM-KKKKEEIYFFF-CONH2 peptide as fluorogenic substrate incubated for 80 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay
Measurement: IC50 = 17.4 nM (pChEMBL 7.760000228881836)
Descriptors: MW 523.54, ALogP 2.36, HBA 8, HBD 2, PSA 120.3, QED 0.36
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(CC(=O)O)CC(F)(F)F)cc1OC
InChIKey: XWGKZKKNJOQUSG-SFHVURJKSA-N
Target: Toll-like receptor 8 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR97
Assay: Human TLR8 Assay: TLR8/NF-kB/SEAPorter HEK 293 Cell Line (Imgenex Corporation) is a stably co-transfected cell line which expresses full-length human TLR8 and the secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NF-κB response element. TLR8 expression in this cell line has been tested by flow cytometry. Transfectants with stable expression were selected using the antibiotic blasticidin and geneticin. TLR signaling leads to the translocation of NF-κB and activation of the promoter results in expression of the SEAP gene. TLR8-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37° C. with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the concentration of compound which produced half of the maximal level of SEAP induction for that compound (EC50).
Measurement: EC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 513.56, ALogP 3.38, HBA 8, HBD 4, PSA 133.83, QED 0.3
Compound (SMILES): C=C(C)C(=O)Nc1ccc(-c2c(-c3ccc(Oc4nccc(C)n4)c(F)c3)c3c(N)ncnc3n2C)cc1
InChIKey: XOQVZSSDIQQUGO-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P22455
Assay: Inhibition of FGFR4 (unknown origin)
Measurement: IC50 = 17633 nM (pChEMBL 4.75)
Descriptors: MW 509.55, ALogP 5.43, HBA 8, HBD 2, PSA 120.84, QED 0.29
Compound (SMILES): Cc1cc(C)c2c(n1)CN(C(=O)CC1CN(c3ccnc(C(F)(F)F)c3)C1)C2
InChIKey: DTCZNKWBDTXEBS-UHFFFAOYSA-N
Target: Muscarinic acetylcholine receptor M1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11229
Assay: Agonist activity at human M1 receptor
Measurement: EC50 > 13300 nM (pChEMBL 4.875999927520752)
Descriptors: MW 390.41, ALogP 3.48, HBA 4, HBD 0, PSA 49.33, QED 0.81
Compound (SMILES): C=CC(=O)Nc1cc(Nc2nccc(Nc3cc(Cl)c(F)cc3C(C)(C)O)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
InChIKey: BTMKEDDEMKKSEF-QGZVFWFLSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR D770_N771insSVD mutant (unknown origin) expressed in human NCI-H2073 cells by ELISA
Measurement: IC50 = 19.95 nM (pChEMBL 7.699999809265137)
Descriptors: MW 584.1, ALogP 5.26, HBA 9, HBD 4, PSA 114.88, QED 0.24
Compound (SMILES): Nc1ncc(-c2ccc([C@@]34C[C@@H]3CN(C3CCOCC3)C4)cc2)cc1C(=O)NC12CCC(O)(CC1)CC2
InChIKey: KPRPFTOLWQQUAV-OCVAFRRMSA-N
Target: Activin receptor type-1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q04771
Assay: ADPGlo Assay: The assays were performed in 384-well, low volume microtiter assay plates in a final reaction volume of 6 ul. Dose-response curves were generated by incubating 10 nM of each kinase in 50 mM Hepes pH 7.5, 0.02% Tween 20, 0.02% BSA, 1 mM DTT, 10 μm Na3VO4, 10 mM β-Glycerolphosphate, 1 mM MgCl2, 12 mM MnCl2 and 15 μm ATP for 60 min at 32° C. in the presence or absence of compound diluted in DMSO. The amount of generated ADP is a measure of kinase activity and is quantified using the ADP-Glo™ Kinase Assay (Promega) according to manufacturer's instructions. ADP is converted to ATP by adding 3 ul of ADP-Glo™ Reagent and incubation at 32° C. for 60 min. ATP is subsequently converted into a bioluminescent signal by adding 6 ul luciferase assay reagents (Kinase detection buffer+Kinase Detection Substrate (Promega)) and further incubation at 32° C. for 60 min. For the measurement of luminescence a PHERAstar™ Multilabel Reader was used at a measurement interval time of 0.1 second (optical module for luminescence measurements in the 230 nm to 750 nm wavelength range).
Measurement: IC50 = 18 nM (pChEMBL 7.75)
Descriptors: MW 502.66, ALogP 3.65, HBA 6, HBD 3, PSA 100.71, QED 0.58
Compound (SMILES): Cn1cc(-c2ccc(CNc3cc(-c4cnc5cc(OCCCN6CCCC6)ccn45)ncn3)cc2)cn1
InChIKey: LVMAULGVWBINFP-UHFFFAOYSA-N
Target: Mast/stem cell growth factor receptor Kit (SINGLE PROTEIN), Homo sapiens
UniProt: P10721
Assay: Inhibition of wild type KIT (unknown origin) using 33P-ATP as substrate incubated for 120 mins by radiometric kinase assay
Measurement: IC50 = 44 nM (pChEMBL 7.360000133514404)
Descriptors: MW 508.63, ALogP 4.67, HBA 9, HBD 1, PSA 85.4, QED 0.27
Compound (SMILES): Cc1ccc([C@H]2C[C@@H]2COc2cc(NCc3nnc(C)s3)nc(C)n2)nc1
InChIKey: WQKPZDLZRFTMTI-CABCVRRESA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 (unknown origin)
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 382.49, ALogP 3.44, HBA 8, HBD 1, PSA 85.71, QED 0.67
Compound (SMILES): Cn1cncc1-c1c(F)cncc1NC(=O)c1c(N)nn2cc(F)cnc12
InChIKey: RBQPCTBFIPVIJN-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition of ATR (unknown origin) assessed as reduction in p53 phosphorylation level incubated for 30 mins by TR-FRET assay
Measurement: IC50 < 1000 nM (pChEMBL 6)
Descriptors: MW 370.32, ALogP 1.64, HBA 8, HBD 2, PSA 116.02, QED 0.57
Compound (SMILES): Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1.O.O
InChIKey: FPKARFMSZDBYQF-ILKKLZGPSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Binding affinity towards human ESR1 in an in vitro cell free assay (CRO assay) measured by membrane filtration
Measurement: AC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 279.19, ALogP -1.66, HBA 7, HBD 4, PSA 147.9, QED 0.45
Compound (SMILES): COc1cc2ncc3c(c2cc1-c1cn(C)nc1C)n(-c1c(F)cncc1OC)c(=O)n3C
InChIKey: WNEFOSMCGCLLJU-UHFFFAOYSA-N
Target: PI3-kinase p110-delta/p85-alpha (PROTEIN COMPLEX), Homo sapiens
UniProt: O00329
Assay: PI3K p110beta/p85alpha (Human), Non-radioactive Assay: PI3K p110β/p85α (human) was incubated in an assay buffer comprising 10 μM phosphati-dylinositol 4,5-bisphosphate and MgATP (concentration as necessary). The reaction was initiated by addition of MgATP solution. After an incubation time of 30 min at room temperature, the reaction was stopped by addition of a solution consisting of EDTA and biotinylated phosphatidylinositol 3,4,5-trisphosphate. Finally, the detection buffer, consisting of a europium-labelled anti-GST monoclonal antibody, a GST-labelled GRP1 PH domain and streptavidin allophycocyanin, was added. The plate was read out via homogeneous time-resolved fluorescence (HTRF) and the corresponding signals were evaluated via the formula HTRF=10000×(Em665nm/Em620nm).
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 448.46, ALogP 3.14, HBA 9, HBD 0, PSA 88.99, QED 0.42
Compound (SMILES): C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@](COc7ncccc7C#N)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
InChIKey: PQBROJOHKLMPKM-WJGXRGGQSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of CYP2C19 (unknown origin)
Measurement: IC50 > 4400 nM (pChEMBL 5.35699987411499)
Descriptors: MW 827.19, ALogP 8.78, HBA 8, HBD 2, PSA 132.62, QED 0.22
Compound (SMILES): CC(C)c1ccc(N(C)c2ccc3c(c2)OCC[C@H]3CNc2cnccc2C(=O)O)cc1
InChIKey: NDVITLLKZQXKGU-IBGZPJMESA-N
Target: Lysine-specific demethylase 4C (SINGLE PROTEIN), Homo sapiens
UniProt: Q9H3R0
Assay: Inhibition of KDM4C (unknown origin)
Measurement: IC50 = 41 nM (pChEMBL 7.389999866485596)
Descriptors: MW 431.54, ALogP 5.65, HBA 5, HBD 2, PSA 74.69, QED 0.5
Compound (SMILES): C=CC(=O)N1CCN(c2c(C#N)c(=O)n(-c3c(C)ccnc3C(C)C)c3nc(-c4c(N)c(F)c(F)c(F)c4F)c(Cl)cc23)CC1
InChIKey: QRRJEUIQLZNPIO-UHFFFAOYSA-N
Target: Cytochrome P450 2C9 (SINGLE PROTEIN), Homo sapiens
UniProt: P11712
Assay: Inhibition of CYP2C9 (unknown origin)
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 640.04, ALogP 5.38, HBA 8, HBD 1, PSA 121.14, QED 0.1
Compound (SMILES): COc1cc(N[C@H](C(=O)c2c[nH]c3ccc(OC(F)(F)F)cc23)c2ccc(Cl)cc2OC)cc(S(C)(=O)=O)c1
InChIKey: QNOPDDHSGQQLCV-DEOSSOPVSA-N
Target: Cytochrome P450 2C19 (SINGLE PROTEIN), Homo sapiens
UniProt: P33261
Assay: Inhibition of human CYP2C19 preincubated for 5 mins followed by NADPH addition measured after 5 to 30 mins by LC-MS analysis
Measurement: IC50 = 10300 nM (pChEMBL 4.989999771118164)
Descriptors: MW 582.98, ALogP 6.18, HBA 7, HBD 2, PSA 106.72, QED 0.23
Compound (SMILES): C=CC(=O)N1C[C@@H](n2nc(C#Cc3c(F)cc4c(ncn4C4CC4)c3F)c(C(N)=O)c2NC)C[C@@H]1COC
InChIKey: YXVDEILMUVTDMK-JKSUJKDBSA-N
Target: Fibroblast growth factor receptor 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P22607
Assay: Inhibition of wild type FGFR3 (unknown origin) using 5-FAM-KKKKEEIYFFF-CONH2 peptide as fluorogenic substrate incubated for 80 mins in presence of ATP by fluorescence-based microfluidic mobility shift assay
Measurement: IC50 = 9.3 nM (pChEMBL 8.029999732971191)
Descriptors: MW 523.54, ALogP 2.36, HBA 8, HBD 2, PSA 120.3, QED 0.36