@article{c955b859372e4b77b66f896383821b55,
title = "The kinase polypharmacology landscape of clinical PARP inhibitors",
abstract = "Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.",
author = "Antolin, {Albert A.} and Malaka Ameratunga and Udai Banerji and Clarke, {Paul A.} and Paul Workman and Bissan Al-Lazikani",
note = "Funding Information: A.A.A. is primarily supported by a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship (204735/Z/16/Z); the People Programme (Marie Curie Actions) of the 7th Framework Programme of the European Union (FP7/2007–2013) under REA grant agreement no. 600388 (TECNIOspring programme) and the Agency of Business Competitiveness of the Government of Catalonia, ACCIO; B.A.-L., P.C. and P.W. are funded a Cancer Research CRUK programme grant to the Cancer Research UK Cancer Therapeutics Unit (grant C309/A11566), a Wellcome Trust biomedical resource and technology grant to develop the Chemical Probes Portal (212969/Z/18/Z) and a Cancer Research UK (CRUK) Drug Discovery Committee strategic award to develop canSAR (C35696/A23187). P.W. is a CRUK Life Fellow. P.W. and B.A.L. are members of the CRUK ICR/ Imperial Convergence Science Centre. We acknowledge support from CRUK and the NHS funding to the CRUK Centre and Biomedical Research Centre respectively at the ICR and Royal Marsden NHS Foundation Trust. The authors thank many colleagues and collaborators for discussions and valuable input into the preparation of this manuscript. In particular, the authors thank Johann de Bono for valuable discussions and advice. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41598-020-59074-4",
language = "English (US)",
volume = "10",
journal = "Scientific reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}