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Evolution of kinase polypharmacology across HSP90 drug discovery.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2021 Oct 21; Vol. 28 (10), pp. 1433-1445.e3. Date of Electronic Publication: 2021 Jun 01. - Publication Year :
- 2021
-
Abstract
- Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared with other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.<br />Competing Interests: Declaration of interests A.A.A., P.A.C., I.C., P.W., and B.A.-L. are/were employees of The Institute of Cancer Research (ICR), which has a commercial interest in a range of drug targets, including HSP90 and protein kinases. P.W., P.A.C., and I.C. were involved in the discovery of luminespib, which was funded by Vernalis and Cancer Research UK. The ICR operates a Rewards to Inventors scheme whereby employees of the ICR may receive financial benefit following commercial licensing of a project. P.W. is a consultant/scientific advisory board member for Nextech Invest Ltd, Storm Therapeutics, Astex Pharmaceuticals, Black Diamond, and CV6, and holds stock in Chroma Therapeutics, NextInvest, Black Diamond, and Storm Therapeutics; he is also a non-executive director of Storm Therapeutics and the Royal Marsden NHS Trust; a board member and executive director of the non-profit Chemical Probes Portal; and a former employee of AstraZeneca. P.W. has received research funding from Vernalis, Astex Therapeutics, Merck KGaA, Sixth Element Capital/CRT Pioneer Fund. B.A.-L. is/was a consultant/scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, and Astellas Pharma, and is an ex-employee of Inpharmatica Ltd. A.A.A., B.A.-L., and P.W. have been instrumental in the creation/development of canSAR and Probe Miner. B.A.-L. was instrumental in the creation of ChEMBL and is a director of the non-profit Chemical Probes Portal. I.C. is/was a consultant to Epidarex LLP, AdoRx Therapeutics, and Enterprise Therapeutics, and is a director of the non-profit Chemical Probes Portal. I.C. has received research funding from Astex, Merck KGaA, Janssen Biopharma, Monte Rosa Therapeutics, and Sixth Element Capital/CRT Pioneer Fund. I.C. holds stock in Monte Rosa Therapeutics AG and is a former employee of Merck Sharp & Dohme.<br /> (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Binding Sites
Discoidin Domain Receptor 1 antagonists & inhibitors
Discoidin Domain Receptor 1 metabolism
HSP90 Heat-Shock Proteins antagonists & inhibitors
Humans
Isoxazoles chemistry
Isoxazoles metabolism
Molecular Docking Simulation
Protein Kinase Inhibitors chemistry
Proto-Oncogene Proteins c-abl antagonists & inhibitors
Proto-Oncogene Proteins c-abl metabolism
Resorcinols chemistry
Resorcinols metabolism
Triazoles chemistry
Triazoles metabolism
Drug Discovery
Evolution, Molecular
HSP90 Heat-Shock Proteins metabolism
Protein Kinase Inhibitors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 28
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 34077750
- Full Text :
- https://doi.org/10.1016/j.chembiol.2021.05.004