HRS-1167 (M9466): A Comprehensive Profile of a Next-Generation Selective PARP1 Inhibitor Poised to Redefine a Class

Executive Summary

HRS-1167, also identified as M9466, is an investigational, orally bioavailable, next-generation small molecule inhibitor of Poly (ADP-Ribose) Polymerase 1 (PARP1).[1] Originally developed by Jiangsu Hengrui Pharmaceuticals, the asset is now under global co-development with Merck KGaA following a landmark licensing agreement, underscoring its significant perceived potential in the oncology landscape.[3] The fundamental value proposition of HRS-1167 is rooted in a highly rational drug design strategy: to retain and potentially enhance the profound antitumor efficacy characteristic of the PARP inhibitor class while concurrently mitigating the dose-limiting hematological toxicities that have constrained the therapeutic window and combination potential of first-generation dual PARP1/2 inhibitors.[5]

This strategic objective is substantiated by a compelling preclinical evidence package, most notably the demonstration of a 672-fold selectivity for PARP1 over PARP2, the enzyme isoform strongly implicated in myelosuppression.[5] This high degree of selectivity is hypothesized to uncouple the desired on-target antitumor effects from the off-target toxicities. Early clinical data from the first-in-human Phase 1 monotherapy study (NCT05473624) have provided powerful validation for this approach. In a heavily pretreated patient population with advanced solid tumors harboring Homologous Recombination Repair (HRR) mutations, HRS-1167 demonstrated a remarkable preliminary objective response rate (ORR) of 41.7%.[6] This efficacy signal is particularly noteworthy given that the study population included patients who had previously progressed on other PARP inhibitors. Furthermore, the drug was well-tolerated, with a manageable safety profile and no maximum tolerated dose reached, lending clinical support to the preclinic