Identification of differential biological activity and synergy between the PARP inhibitor rucaparib and its major metabolite.

The (poly)pharmacology of drug metabolites is seldom comprehensively characterized in drug discovery. However, some drug metabolites can reach high plasma concentrations and display in vivo activity. Here, we use computational and experimental methods to comprehensively characterize the kinase polypharmacology of M324, the major metabolite of the PARP1 inhibitor rucaparib. We demonstrate that M324 displays unique PLK2 inhibition at clinical concentrations. This kinase activity could have implications for the efficacy and safety of rucaparib and therefore warrants further clinical investigation. Importantly, we identify synergy between the drug and the metabolite in prostate cancer models and a complete reduction of α-synuclein accumulation in Parkinson's disease models. These activities could be harnessed in the clinic or open new drug discovery opportunities. The study reported here highlights the importance of characterizing the activity of drug metabolites to comprehensively understand drug response in the clinic and exploit our current drug arsenal in precision medicine.

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests 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.