PARP-1 selective inhibitors: A new direction in drug discovery to improve the therapeutic index of PARP-targeted cancer therapy.

Poly(ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination deficiency, but are limited by hematological toxicity and poor discrimination between PARP1 and PARP2. Because PARP1 drives most antitumor PARylation and trapping, whereas PARP2 contributes to hematopoietic maintenance, selective PARP1 inhibition might widen the therapeutic window. Emerging agents, including saruparib and palacaparib, confirm that strong isoform selectivity can coexist with cellular target engagement, tissue exposure, and antitumor activity. However, biochemical selectivity alone is insufficient. Clinical differentiation requires matched comparisons of efficacy, unbound exposure, trapping, dose intensity, and marrow recovery. PARP1 selectivity remains a promising, but not yet proven, strategy for safer and more durable therapy.