The off-target kinase landscape of clinical PARP inhibitors

Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet there are several clinical settings where no strong rationale exists to inform clinicians on which to choose in terms of clinical effectiveness and toxicity. 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. We previously hypothesized that PARP inhibitors could have an inherent capacity to inhibit kinases off-target. Here, we characterise 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 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, including use of PARP inhibitors in combination with other agents, including immunotherapy.