NMS-P118

To explore the molecular determinants of ligand selectivity, we focus on four clinically relevant PARP inhibitors-two PARP1-selective (saruparib and NMS-P118) and two non-selective (veliparib and olaparib) inhibitors-and perform atomistic potential-of-mean-force calculations of the PARP1 catalytic binding domain in the presence of these molecules. Progressively increasing the number of mutations markedly reduces binding stability, with distinct residue combinations exerting two primary effects: destabilization of the final bound state and the emergence of energetic barriers along the ligand association pathway. Together, our results provide a coherent mechanistic framework for understanding PARP1 selectivity and informs the rational design of next-generation inhibitors with improved efficacy and safety.

Since the approval of olaparib in 2014 for BRCA mutated (BRCAm) ovarian cancer, many PARP inhibitors have been developed and have seen widespread success...The publication of NMS-P118 in 2015 by Nerviano Medical Sciences showed that a highly selective PARP1 inhibitor could be found...The secondary pharmacology of AZD5305 is remarkably clean, with hERG activity >40 µM. AZD5305 has a very favorable pre-clinical PK profile, low predicted human dose, and has shown efficacy in an MDA-MB-436 mouse xenograft model.