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.
Collections
Subject
Humans
Neoplasms
Piperazines
Piperidines
Indazoles
Phthalazines
Indoles
Isoenzymes
Protein-Serine-Threonine Kinases
Cyclin-Dependent Kinases
Proto-Oncogene Proteins
Antineoplastic Agents
Binding Sites
Protein Structure, Secondary
Protein Binding
Substrate Specificity
Protein-Tyrosine Kinases
Protein Interaction Domains and Motifs
HEK293 Cells
Molecular Docking Simulation
Polypharmacology
Poly(ADP-ribose) Polymerase Inhibitors
Poly (ADP-Ribose) Polymerase-1
Research team
Computational Biology and Chemogenomics
Signal Transduction & Molecular Pharmacology
Clinical Pharmacology – Adaptive Therapy
Language
eng
Date accepted
2020-01-21
License start date
2020-02-17
Citation
Scientific reports, 2020, 10 (1), pp. 2585 - ?
Publisher
NATURE PORTFOLIO
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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