Beyond Catalytic Inhibition: The Evolving Landscape of PARP Pharmacology.

Abstract

Since the identification of PARP1/2 as synthetic lethal targets in BRCA-deficient breast cancer and the subsequent approval of catalytic domain-targeting PARP inhibitors, the landscape of PARP inhibitors has expanded to encompass a broader chemical tool kit. Beyond PARP1/2's canonical role in DNA repair, PARP inhibitors have revealed context-dependent PARP functions in anticancer immunity, viral infection, neurodegeneration, and cellular organization. These discoveries have motivated new strategies that extend past targeting catalytic domains. In this review, we highlight three emerging directions: (a) biological insights revealed by PARP1/2 inhibitors in oncology and other settings, (b) progress in developing inhibitors against PARP family members beyond PARP1/2, and (c) approaches that target noncatalytic domains or modulate PARP function through mechanisms such as interface disruption and targeted degradation. We conclude by outlining key next steps for advancing PARP pharmacology, including substrate mapping, utilizing rational polypharmacology, targeting ADP-ribose readers and erasers, and expanding structural coverage of PARP family proteins.