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.

在药物发现中很少全面表征药物代谢物的（多）药理学。然而，一些药物代谢物可以达到高血浆浓度并表现出体内活性。在这里，我们使用计算和实验方法来全面表征 M324（PARP1 抑制剂 rucaparib 的主要代谢物）的激酶多药理学。我们证明 M324 在临床浓度下表现出独特的 PLK2 抑制作用。这种激酶活性可能对 rucaparib 的功效和安全性产生影响，因此值得进一步的临床研究。重要的是，我们确定了前列腺癌模型中药物和代谢物之间的协同作用，以及帕金森病模型中 α-突触核蛋白积累的完全减少。这些活动可以在临床中利用或开辟新药发现的机会。这里报告的研究强调了表征药物代谢物活性的重要性，以全面了解临床药物反应并利用我们当前精准医学中的药物库。