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 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 to other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimisation to discover luminespib and that the hit, leads and clinical candidate all have different polypharmacological profiles. We conclude that the submicromolar target inhibition of protein kinases by ganetespib may have potential clinical significance and we recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.
Competing Interest Statement
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. 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 and a Director of the non-profit Chemical Probes Portal. B.A.-L. is/was a consultant/ scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, 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. 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.
Footnotes
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