|
Binding affinity to Hsp90 N-terminal ATPase domain by isothermal titration calorimetry assay
|
None
|
0.71
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Cytotoxicity against human HCT116 cells by Alamar blue assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Inhibition of human ERG expressed in HEK293 cells at 3 uM by patch clamp assay
|
Homo sapiens
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Inhibition of human ERG expressed in HEK293 cells at 30 uM by patch clamp assay
|
Homo sapiens
|
42.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Inhibition of CYP2C9 at 10 uM
|
None
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Inhibition of CYP2C19 at 10 uM
|
None
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Antitumor activity against human HCT116 cells xenografted in BALB/c mouse assessed as inhibition of tumor growth at 60 mg/kg, ip qd for 3 days then no dose for 3 days for four dosing cycles measured on day 21
|
Homo sapiens
|
78.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Antitumor activity against human HCT116 cells xenografted in BALB/c mouse assessed as inhibition of tumor growth at 60 mg/kg, ip qd for 3 days then no dose for 3 days for four dosing cycles measured on day 21 relative to control
|
Homo sapiens
|
22.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
Year : 2010
Volume : 53
Issue : 16
First Page : 5956
Last Page : 5969
Authors : Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ.
Abstract : Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
|
Inhibition of HSP90 (unknown origin)-mediated ATPase activity at 40 uM after 3 hrs by malachite green assay relative to control
|
Homo sapiens
|
91.02
%
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Inhibition of full-length HSP90 (unknown origin) expressed in Escherichia coli assessed as inhibition of ATPase activity after 3 hrs by spectrophotometric analysis
|
Homo sapiens
|
350.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Displacement of FITC-geldanamycin from HSP90 (unknown origin) after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Antiproliferative activity against human SKBR3 cells after 48 hrs by MTT assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Antiproliferative activity against human MCF7 cells after 48 hrs by MTT assay
|
Homo sapiens
|
280.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Antiproliferative activity against human HCT116 cells after 48 hrs by MTT assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.
Year : 2014
Volume : 79
First Page : 399
Last Page : 412
Authors : Sun HP, Jia JM, Jiang F, Xu XL, Liu F, Guo XK, Cherfaoui B, Huang HZ, Pan Y, You QD.
Abstract : Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 μM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
|
Inhibition of FITC-geldanamycin binding to N-terminal GST-tagged Hsp90 (unknown origin) expressed in Escherichia coli at 100 uM measured after 15 mins by fluorescence polarization assay relative to control
|
Homo sapiens
|
99.8
%
|
|
Journal : Bioorg Med Chem
Title : Optimization and bioevaluation of Cdc37-derived peptides: An insight into Hsp90-Cdc37 protein-protein interaction modulators.
Year : 2017
Volume : 25
Issue : 1
First Page : 233
Last Page : 240
Authors : Wang L, Li L, Fu WT, Jiang ZY, You QD, Xu XL.
Abstract : Targeting Hsp90-Cdc37 protein-protein interaction (PPI) is becoming an alternative approach for future anti-cancer drug development. We previously reported the discovery of an eleven-residue peptide (Pep-1) with micromolar activity for the disruption of Hsp90-Cdc37 PPI. Efforts to improve upon the Pep-1 led to the discovery of more potent modulators for Hsp90-Cdc37 PPI. Through the analysis of peptides binding patterns, more peptides were designed for further verification which resulted in Pep-5, the shortest peptide targeting Hsp90-Cdc37, exerting the optimal structure and the most efficient binding mode. Subsequent MD simulation analysis also confirmed that Pep-5 could perform more stable binding ability and better ligand properties than Pep-1. Under the premise of retentive binding capacity, Pep-5 exhibited lower molecular weight and higher ligand efficiency with a Kd value of 5.99μM (Pep-1 Kd=6.90μM) in both direct binding determination and biological evaluation. The optimal and shortest Pep-5 might provide a breakthrough and a better model for the future design of small molecule inhibitors targeting Hsp90-Cdc37 PPI.
|
Antiproliferative activity against human MCF7 cells incubated for 72 hrs by MTT assay
|
Homo sapiens
|
32.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification and optimization of novel 6-acylamino-2-aminoquinolines as potent Hsp90 C-terminal inhibitors.
Year : 2017
Volume : 141
First Page : 1
Last Page : 14
Authors : Jiang F, Guo AP, Xu JC, Wang HJ, Mo XF, You QD, Xu XL.
Abstract : In order to discover novel Hsp90 inhibitors targeting the C-terminal ATP binding pocket, a novobiocin derivative based ROCS model was constructed for virtual screening. Compound 13 was identified as the lead compound and then systematical structure activity relationship (SAR) study was conducted. These efforts led to compound 69, which exhibited potent anti-proliferative activities against MCF7 and SKBr3 breast cancer cell lines. In 4T1 mice breast cancer models, 69 exhibited potent tumor growth inhibition and anti-metastasis effect. Compound 69 as a potent antitumor agent targeting the Hsp90 C-terminal is worthy of further pre-clinical study.
|
Antiproliferative activity against human SKBR3 cells incubated for 72 hrs by MTT assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification and optimization of novel 6-acylamino-2-aminoquinolines as potent Hsp90 C-terminal inhibitors.
Year : 2017
Volume : 141
First Page : 1
Last Page : 14
Authors : Jiang F, Guo AP, Xu JC, Wang HJ, Mo XF, You QD, Xu XL.
Abstract : In order to discover novel Hsp90 inhibitors targeting the C-terminal ATP binding pocket, a novobiocin derivative based ROCS model was constructed for virtual screening. Compound 13 was identified as the lead compound and then systematical structure activity relationship (SAR) study was conducted. These efforts led to compound 69, which exhibited potent anti-proliferative activities against MCF7 and SKBr3 breast cancer cell lines. In 4T1 mice breast cancer models, 69 exhibited potent tumor growth inhibition and anti-metastasis effect. Compound 69 as a potent antitumor agent targeting the Hsp90 C-terminal is worthy of further pre-clinical study.
|
Inhibition of FITC-labeled geldanamycin binding to recombinant HSP90alpha (unknown origin) after 1 hr by fluorescence polarization assay
|
Homo sapiens
|
13.6
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs.
Year : 2018
Volume : 152
First Page : 76
Last Page : 86
Authors : Geng K, Liu H, Song Z, Zhang C, Zhang M, Yang H, Cao J, Geng M, Shen A, Zhang A.
Abstract : Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (17.3 vs 9.8 nM) and Hsp90α (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALKL1196M. Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AKT, and up-regulation of the chaperone protein Hsp70 in H3122 cells.
|
Antiproliferative activity against human NCI-H3122 cells after 72 hrs by SRB assay
|
Homo sapiens
|
52.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs.
Year : 2018
Volume : 152
First Page : 76
Last Page : 86
Authors : Geng K, Liu H, Song Z, Zhang C, Zhang M, Yang H, Cao J, Geng M, Shen A, Zhang A.
Abstract : Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (17.3 vs 9.8 nM) and Hsp90α (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALKL1196M. Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AKT, and up-regulation of the chaperone protein Hsp70 in H3122 cells.
|
Inhibition of FITC-geldanamycin binding to dog GST-tagged GRP94 N41 deletion mutant (69 to 337 residues) expressed in Escherichia coli BL21star (DE3) at 100 uM after 4 hrs by FP assay relative to control
|
Canis lupus familiaris
|
100.0
%
|
|
Journal : J Med Chem
Title : Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis.
Year : 2018
Volume : 61
Issue : 21
First Page : 9513
Last Page : 9533
Authors : Jiang F, Guo AP, Xu JC, You QD, Xu XL.
Abstract : As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.
|
Inhibition of FITC-geldanamycin binding to dog GST-tagged GRP94 N41 deletion mutant (69 to 337 residues) expressed in Escherichia coli BL21star (DE3) after 4 hrs by GM-FITC-based FP assay
|
Canis lupus familiaris
|
20.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis.
Year : 2018
Volume : 61
Issue : 21
First Page : 9513
Last Page : 9533
Authors : Jiang F, Guo AP, Xu JC, You QD, Xu XL.
Abstract : As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.
|
Inhibition of FITC-geldanamycin binding to human His-tagged HSP90alpha N-terminal domain (1 to 236 residues) expressed in Escherichia coli BL21star (DE3) after 4 hrs by FP assay relative to control
|
Homo sapiens
|
22.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis.
Year : 2018
Volume : 61
Issue : 21
First Page : 9513
Last Page : 9533
Authors : Jiang F, Guo AP, Xu JC, You QD, Xu XL.
Abstract : As the endoplasmic reticulum paralogue of Hsp90, Grp94 chaperones a small set of client proteins associated with some diseases, including cancer, primary open-angle glaucoma, and inflammatory disorders. Grp94-selective inhibition has been a potential therapeutic strategy for these diseases. In this study, inspired by the conclusion that ligand-induced "Phe199 shift" effect is the structural basis of Grp94-selective inhibition, a series of novel Grp94 selective inhibitors incorporating "benzamide" moiety were developed, among which compound 54 manifested the most potent Grp94 inhibitory activity with an IC50 value of 2 nM and over 1000-fold selectivity to Grp94 against Hsp90α. In a DSS-induced mouse model of ulcerative colitis (UC), compound 54 exhibited significant anti-inflammatory efficacy. This work provides a potent Grp94 selective inhibitor as probe compound for the biological study of Grp94 and represents the first study that confirms the potential therapeutic efficacy of Grp94-selective inhibitors against UC.
|
IC50 for antiviral activity against SARS-CoV-2 in the Vero E6 cell line at 48 h by immunofluorescence-based assay (detecting the viral NP protein in the nucleus of the Vero E6 cells).
|
Chlorocebus sabaeus
|
154.88
nM
|
|
Journal : Nature
Title : A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
Year : 2020
Authors : David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Kris M White, Matthew J O'Meara, Veronica V Rezelj, Jeffrey Z Guo, Danielle L Swaney, et al
Abstract : The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
109.92
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Antiproliferative activity against human NCI-H1299 cells after 72 hrs by MTT assay
|
Homo sapiens
|
370.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors.
Year : 2019
Volume : 167
First Page : 485
Last Page : 498
Authors : Yao H, Xu F, Wang G, Xie S, Li W, Yao H, Ma C, Zhu Z, Xu J, Xu S.
Abstract : A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.
|
Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors.
Year : 2019
Volume : 167
First Page : 485
Last Page : 498
Authors : Yao H, Xu F, Wang G, Xie S, Li W, Yao H, Ma C, Zhu Z, Xu J, Xu S.
Abstract : A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.
|
Antiproliferative activity against human A549 cells after 72 hrs by MTT assay
|
Homo sapiens
|
440.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors.
Year : 2019
Volume : 167
First Page : 485
Last Page : 498
Authors : Yao H, Xu F, Wang G, Xie S, Li W, Yao H, Ma C, Zhu Z, Xu J, Xu S.
Abstract : A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.
|
Inhibition of FITC-geldanamycin binding to recombinant human full-length C-terminal His-tagged HSP90alpha N-terminal domain (1 to 732 residues) expressed in Escherichia coli after 1 hr by fluorescence polarization assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors.
Year : 2019
Volume : 167
First Page : 485
Last Page : 498
Authors : Yao H, Xu F, Wang G, Xie S, Li W, Yao H, Ma C, Zhu Z, Xu J, Xu S.
Abstract : A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors.
|
Inhibition of recombinant full-length HSP90 ATPase activity N-terminal domain (9 to 236 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) measured after 1 hr by ADP hunter plus assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer.
Year : 2020
Volume : 63
Issue : 3
First Page : 1281
Last Page : 1297
Authors : Wang L, Jiang J, Zhang L, Zhang Q, Zhou J, Li L, Xu X, You Q.
Abstract : Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (Kd = 0.5 μM) and cellular inhibitory activity (IC50 = 1.73 μM). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.
|
Cytotoxicity against imatinib-resistant human GIST430 cells assessed as decrease in cell viability after 7 days by alamar blue assay
|
Homo sapiens
|
34.0
nM
|
|
Journal : J Med Chem
Title : Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.
Year : 2016
Volume : 59
Issue : 12
First Page : 5563
Last Page : 5586
Authors : Wang M, Shen A, Zhang C, Song Z, Ai J, Liu H, Sun L, Ding J, Geng M, Zhang A.
Abstract : Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.
|
Cytotoxicity against imatinib-resistant human GIST48 cells assessed as decrease in cell viability after 7 days by alamar blue assay
|
Homo sapiens
|
55.0
nM
|
|
Journal : J Med Chem
Title : Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.
Year : 2016
Volume : 59
Issue : 12
First Page : 5563
Last Page : 5586
Authors : Wang M, Shen A, Zhang C, Song Z, Ai J, Liu H, Sun L, Ding J, Geng M, Zhang A.
Abstract : Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-3.297
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.3
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.3
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Displacement of FITC-geldanamycin from N-terminal HSP90alpha (unknown origin) after 30 mins by fluorescence polarization competitive binding assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human HCT-116 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
70.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human MCF7 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Displacement of FITC-geldanamycin from N-terminal GRP94 (unknown origin) after 30 mins by fluorescence polarization competitive binding assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human MDA-MB-231 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
38.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human MDA-MB-468 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
66.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human SK-BR-3 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
71.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human T47D assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
24.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human BT-474 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
32.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human U2OS assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
67.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human MKN-28 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
129.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human A549 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human HepG2 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human K562 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
38.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Antiproliferative activity against human MV4-11 assessed as reduction in cell viability incubated for 72 hrs by MTT assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Inhibition of GST-tagged dog GRP94 (69 to 337 residues) expressed in Escherichia coli BL21 (DE3) at 100 uM measured after 4 hrs by fluorescent polarization assay relative to control
|
Canis lupus familiaris
|
100.0
%
|
|
|
Inhibition of GST-tagged dog GRP94 (69 to 337 residues) expressed in Escherichia coli BL21 (DE3) measured after 4 hrs by fluorescent polarization assay
|
Canis lupus familiaris
|
13.0
nM
|
|
|
Inhibition of Hsp90alpha (unknown origin) at 100 uM by fluorescent polarization assay relative to control
|
Homo sapiens
|
100.0
%
|
|
