Evolution of kinase polypharmacology across HSP90 drug discovery.
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Embargo End Date
Authors
Antolin, AA
Clarke, PA
Collins, I
Workman, P
Al-Lazikani, B
Clarke, PA
Collins, I
Workman, P
Al-Lazikani, B
Document Type
Journal Article
Date
2021-10-21
Date Accepted
2021-05-05
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.
Citation
Cell chemical biology, 2021
Source Title
Publisher
CELL PRESS
ISSN
2451-9456
eISSN
2451-9448
Collections
Research Team
Computational Biology and Chemogenomics
Medicinal Chemistry 2
Signal Transduction & Molecular Pharmacology
Computational Biology and Chemogenomics
Medicinal Chemistry 2
Signal Transduction & Molecular Pharmacology
Medicinal Chemistry 2
Signal Transduction & Molecular Pharmacology
Computational Biology and Chemogenomics
Medicinal Chemistry 2
Signal Transduction & Molecular Pharmacology