Identification of differential polypharmacology between the PARP inhibitor rucaparib and its major metabolite

The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery and development. However, some drug metabolites can reach high plasma concentrations and display relevant in vivo activity, which can be distinct from its parent drug. Here, we use computational and experimental methods to comprehensively characterise the kinase polypharmacology of M324, the major metabolite of the FDA-approved PARP inhibitor rucaparib. We experimentally demonstrate that M324 displays a distinct in vitro kinome profile from its parent drug, characterized by potent in vitro inhibition of GSK3A and PLK2 at clinically-relevant concentrations. These confirmed kinase activities of M324 could have potential implications for the efficacy and safety of rucaparib and therefore warrant further clinical investigation. The study reported here highlights the importance of thoroughly characterizing the activity of significant drug metabolites to better understanding drug responses in the clinic and maximally exploit the current drug arsenal in personalized and precision medicine. ### Competing Interest Statement A.A.A. and H.H. are/were employees of The Institute of Cancer Research (ICR), which has a commercial interest in a range of drug targets, including PARP and protein kinases. The ICR operates a Rewards to Inventors scheme whereby employees of the ICR may receive financial benefit following commercial licensing of a project. A.A.A. has been instrumental in the creation/development of canSAR, the Chemical Probes Portal and Probe Miner. A.A.A. is/was a consultant of DarwinHealth, Inc.