Targeting PARP1: A Promising Approach for Next-Generation Poly (ADP-ribose) Polymerase Inhibitors

PARPis have demonstrated efficacy in BRCA-mutated cancers deficient in homologous recombination repair. Furthermore, PARPis have shown efficacy in BRCA-wild-type cancers with a homologous recombination deficiency phenotype known as BRCAness. Current clinically approved PARPis inhibit both PARP1 and PARP2, and their clinical promise is limited by toxicity, resistance, and a lack of combination partners.

PARP2 inhibition is associated with hematological toxicity, affecting the tolerability and efficacy of monotherapy and combination therapies. Furthermore, synthetic lethality in BRCA-mutated cancers depends mostly on PARP1, whereas PARP2 is not essential. These findings promoted the development of next-generation PARPis with greater selectivity for PARP1 than for PARP2.

In this review, we discuss the next-generation PARPis that target PARP1 and show promise in terms of improved safety, tolerability, pharmacological profiles, and efficacy compared to existing clinically approved PARPis. These next-generation PARP1-selective inhibitors hold significant promises for improving the survival and outcomes of cancer patients.