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Evolution of kinase polypharmacology across HSP90 drug discovery.

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.

SUBMITTER: Antolin AA

PROVIDER: S-EPMC8550792 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Evolution of kinase polypharmacology across HSP90 drug discovery.

Antolin Albert A AA Clarke Paul A PA Collins Ian I Workman Paul P Al-Lazikani Bissan B

Cell chemical biology 20210601 10

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 o ...[more]

PMID: 34077750

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