lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): COc1cc(-c2ccc(OCc3ccccc3)c(F)c2)cc(C=O)c1O
InChIKey: OKZPSPQQUHWJBL-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 5550 nM (pChEMBL 5.260000228881836)
Descriptors: MW 352.36, ALogP 4.6, HBA 4, HBD 1, PSA 55.76, QED 0.66
Compound (SMILES): COc1cc(-c2ccc(Oc3ccccc3)cc2)cc(C=O)c1O
InChIKey: DKQXALSDCVZDGN-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 6340 nM (pChEMBL 5.199999809265137)
Descriptors: MW 320.34, ALogP 4.67, HBA 4, HBD 1, PSA 55.76, QED 0.69
Compound (SMILES): O=Cc1cc(Br)cc([N+](=O)[O-])c1O
InChIKey: YEYPSUQQZNDKDE-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 6600 nM (pChEMBL 5.179999828338623)
Descriptors: MW 246.02, ALogP 1.88, HBA 4, HBD 1, PSA 80.44, QED 0.49
Compound (SMILES): COc1cc(O)c(C=O)c(OC)c1
InChIKey: FQRQWPNYJOFDLO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 6830 nM (pChEMBL 5.170000076293945)
Descriptors: MW 182.18, ALogP 1.22, HBA 4, HBD 1, PSA 55.76, QED 0.71
Compound (SMILES): COc1ccc(-c2ccncc2)c(C=O)c1O
InChIKey: CYNABUBZNGLJBG-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 7550 nM (pChEMBL 5.119999885559082)
Descriptors: MW 229.24, ALogP 2.28, HBA 4, HBD 1, PSA 59.42, QED 0.82
Compound (SMILES): COc1ccc(-c2ccc(C(C)C)cc2)c(C=O)c1O
InChIKey: YEDVCHKANJNDGC-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 8200 nM (pChEMBL 5.090000152587891)
Descriptors: MW 270.33, ALogP 4, HBA 3, HBD 1, PSA 46.53, QED 0.85
Compound (SMILES): COc1cc(-c2ccccc2OCc2ccccc2)cc(C=O)c1O
InChIKey: PZQXCKRGJIWFQQ-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 8470 nM (pChEMBL 5.070000171661377)
Descriptors: MW 334.37, ALogP 4.46, HBA 4, HBD 1, PSA 55.76, QED 0.68
Compound (SMILES): COc1ccc(O)c(C=O)c1
InChIKey: FZHSPPYCNDYIKD-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 8850 nM (pChEMBL 5.050000190734863)
Descriptors: MW 152.15, ALogP 1.21, HBA 3, HBD 1, PSA 46.53, QED 0.65
Compound (SMILES): COc1ccc(-c2cc(C=O)c(O)c(OC)c2)c(OC)n1
InChIKey: ITKFLUZILRPLIG-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 9270 nM (pChEMBL 5.03000020980835)
Descriptors: MW 289.29, ALogP 2.29, HBA 6, HBD 1, PSA 77.88, QED 0.85
Compound (SMILES): COc1cc(-c2ccc(C(C)C)cc2)cc(C=O)c1O
InChIKey: CKEGNFJNQVFDKT-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 9400 nM (pChEMBL 5.03000020980835)
Descriptors: MW 270.33, ALogP 4, HBA 3, HBD 1, PSA 46.53, QED 0.85
Compound (SMILES): COc1ccc(-c2ccc3ccccc3c2)c(C=O)c1O
InChIKey: LHSDHWLMLWIIIC-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 9750 nM (pChEMBL 5.010000228881836)
Descriptors: MW 278.31, ALogP 4.03, HBA 3, HBD 1, PSA 46.53, QED 0.74
Compound (SMILES): O=Cc1c(-c2cncnc2)ccc(C(=O)O)c1O
InChIKey: MOOVOTIHKMKJQQ-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 244.21, ALogP 1.36, HBA 5, HBD 2, PSA 100.38, QED 0.79
Compound (SMILES): O=Cc1cc(-c2ccncc2)ccc1O
InChIKey: AWOHFBHWSKCQFQ-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 147 nM (pChEMBL 6.829999923706055)
Descriptors: MW 199.21, ALogP 2.27, HBA 3, HBD 1, PSA 50.19, QED 0.75
Compound (SMILES): O=Cc1cc(-c2cccnc2)cc(F)c1O
InChIKey: NVTGSOKDKHGFDY-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 217.2, ALogP 2.41, HBA 3, HBD 1, PSA 50.19, QED 0.79
Compound (SMILES): COc1cc(-c2cccnc2)cc(C=O)c1O
InChIKey: RXRLTYDBSJJXMV-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 149 nM (pChEMBL 6.829999923706055)
Descriptors: MW 229.24, ALogP 2.28, HBA 4, HBD 1, PSA 59.42, QED 0.82
Compound (SMILES): COc1cc(-c2ccc(C)s2)cc(C=O)c1O
InChIKey: MSVPDYYUKAKQHT-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 743 nM (pChEMBL 6.130000114440918)
Descriptors: MW 248.3, ALogP 3.25, HBA 4, HBD 1, PSA 46.53, QED 0.85
Compound (SMILES): COc1ccc(-c2cc(F)c(O)c(C=O)c2)cn1
InChIKey: OIWKSWFIEZSKTK-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 168 nM (pChEMBL 6.78000020980835)
Descriptors: MW 247.22, ALogP 2.41, HBA 4, HBD 1, PSA 59.42, QED 0.85
Compound (SMILES): COc1cc(-c2ccc(C(C)=O)s2)cc(C=O)c1O
InChIKey: RMXHEBAUEAQDLH-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 97 nM (pChEMBL 7.010000228881836)
Descriptors: MW 276.31, ALogP 3.14, HBA 5, HBD 1, PSA 63.6, QED 0.69
Compound (SMILES): COc1ccc(-c2cc(C=O)c(O)c([N+](=O)[O-])c2)cn1
InChIKey: NXRTXJYJMPSCBE-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 346 nM (pChEMBL 6.460000038146973)
Descriptors: MW 274.23, ALogP 2.18, HBA 6, HBD 1, PSA 102.56, QED 0.52
Compound (SMILES): COc1cc(-c2cccc3ncccc23)cc(C=O)c1O
InChIKey: RCLLQACBAVZRCV-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 932 nM (pChEMBL 6.03000020980835)
Descriptors: MW 279.3, ALogP 3.43, HBA 4, HBD 1, PSA 59.42, QED 0.75
Compound (SMILES): O=Cc1cc(-c2cccc3ncccc23)cc(F)c1O
InChIKey: SUGJWLFOIBWGSP-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 305 nM (pChEMBL 6.519999980926514)
Descriptors: MW 267.26, ALogP 3.56, HBA 3, HBD 1, PSA 50.19, QED 0.72
Compound (SMILES): O=Cc1cc(-c2cccc3ncccc23)cc([N+](=O)[O-])c1O
InChIKey: LFFOXNMZCQIGTC-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 3333 nM (pChEMBL 5.480000019073486)
Descriptors: MW 294.27, ALogP 3.33, HBA 5, HBD 1, PSA 93.33, QED 0.45
Compound (SMILES): COc1cc(-c2cncc3ccccc23)cc(C=O)c1O
InChIKey: MGQHRGRABLFQGB-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 100 nM (pChEMBL 7)
Descriptors: MW 279.3, ALogP 3.43, HBA 4, HBD 1, PSA 59.42, QED 0.75
Compound (SMILES): COc1ccc(-c2cc(C=O)c(O)c(OC)c2)cn1
InChIKey: IIRCXCKUQPKXDG-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 74 nM (pChEMBL 7.130000114440918)
Descriptors: MW 259.26, ALogP 2.28, HBA 5, HBD 1, PSA 68.65, QED 0.85
Compound (SMILES): O=Cc1cc(-c2csc3ccccc23)cc([N+](=O)[O-])c1O
InChIKey: QOJZKZFDRHHCAA-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 2369 nM (pChEMBL 5.619999885559082)
Descriptors: MW 299.31, ALogP 3.99, HBA 5, HBD 1, PSA 80.44, QED 0.45
Compound (SMILES): COc1cc(-c2cc3ccccc3o2)cc(C=O)c1O
InChIKey: LQFZYFMBBNIXEF-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 82 nM (pChEMBL 7.090000152587891)
Descriptors: MW 268.27, ALogP 3.63, HBA 4, HBD 1, PSA 59.67, QED 0.74
Compound (SMILES): Cc1noc(C)c1-c1cc(F)c(O)c(C=O)c1
InChIKey: XLBHNGOZOHQPGZ-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 994 nM (pChEMBL 6)
Descriptors: MW 235.21, ALogP 2.62, HBA 4, HBD 1, PSA 63.33, QED 0.81
Compound (SMILES): O=Cc1cc(-c2ccco2)cc(F)c1O
InChIKey: HNWAWBCRCXFAMK-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 206.17, ALogP 2.6, HBA 3, HBD 1, PSA 50.44, QED 0.77
Compound (SMILES): O=Cc1cc(-c2cccnc2)cc(C(F)(F)F)c1O
InChIKey: RCSCJURTYIPEBO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 800 nM (pChEMBL 6.099999904632568)
Descriptors: MW 267.21, ALogP 3.29, HBA 3, HBD 1, PSA 50.19, QED 0.85
Compound (SMILES): CC(=O)c1ccc(-c2cc(F)c(O)c(C=O)c2)s1
InChIKey: ZHXLJZUTYIVCBD-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 46 nM (pChEMBL 7.340000152587891)
Descriptors: MW 264.28, ALogP 3.27, HBA 4, HBD 1, PSA 54.37, QED 0.68
Compound (SMILES): O=Cc1cc(-c2cncc3ccccc23)cc(F)c1O
InChIKey: QEYDHHUSRXZXAF-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 104 nM (pChEMBL 6.980000019073486)
Descriptors: MW 267.26, ALogP 3.56, HBA 3, HBD 1, PSA 50.19, QED 0.72
Compound (SMILES): O=Cc1cc(-c2cncc3ccccc23)cc([N+](=O)[O-])c1O
InChIKey: AKRDISAFPVXTIL-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 294.27, ALogP 3.33, HBA 5, HBD 1, PSA 93.33, QED 0.45
Compound (SMILES): O=Cc1cc(-c2cncc3ccccc23)cc(C(F)(F)F)c1O
InChIKey: JBTVUOYJAIPGBV-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 164 nM (pChEMBL 6.789999961853027)
Descriptors: MW 317.27, ALogP 4.44, HBA 3, HBD 1, PSA 50.19, QED 0.71
Compound (SMILES): COc1cc(-c2cn[nH]c2)cc(C=O)c1O
InChIKey: WDYNNQXPJNBKNE-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 310 nM (pChEMBL 6.510000228881836)
Descriptors: MW 218.21, ALogP 1.6, HBA 4, HBD 2, PSA 75.21, QED 0.77
Compound (SMILES): Cn1cc(-c2cc(F)c(O)c(C=O)c2)cn1
InChIKey: XAOXIRUBTMMLDX-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 236 nM (pChEMBL 6.630000114440918)
Descriptors: MW 220.2, ALogP 1.74, HBA 4, HBD 1, PSA 55.12, QED 0.78
Compound (SMILES): Cn1cc(-c2cc(C=O)c(O)c([N+](=O)[O-])c2)cn1
InChIKey: YCAWICYVQZBSDC-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 535 nM (pChEMBL 6.269999980926514)
Descriptors: MW 247.21, ALogP 1.51, HBA 6, HBD 1, PSA 98.26, QED 0.5
Compound (SMILES): COC(=O)c1ccc(-c2cc(C=O)c(O)c(OC)c2)cc1
InChIKey: UHSKINGQYRKDLQ-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 286.28, ALogP 2.67, HBA 5, HBD 1, PSA 72.83, QED 0.69
Compound (SMILES): O=Cc1cc(-c2cncnc2)ccc1O
InChIKey: HPQAHGRGPPOWML-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 170 nM (pChEMBL 6.769999980926514)
Descriptors: MW 200.2, ALogP 1.66, HBA 4, HBD 1, PSA 63.08, QED 0.75
Compound (SMILES): COc1cc(-c2cncnc2)cc(C=O)c1O
InChIKey: NJKWZSYIJYLNDO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 39 nM (pChEMBL 7.409999847412109)
Descriptors: MW 230.22, ALogP 1.67, HBA 5, HBD 1, PSA 72.31, QED 0.81