Abstract 1171: M9466 (HRS-1167): A highly potent and selective PARP1 inhibitor with DNA trapping activity, monotherapy antitumor activity and synergistic potential with DDR inhibitors and chemotherapies

Abstract Poly(ADP-ribose) polymerase 1 (PARP1) plays a key role in the repair of single-stranded DNA breaks and DNA damage caused by endogenous replication and repair errors or by exogenous DNA damaging agents. Currently approved PARP inhibitors (PARPis) such as olaparib, niraparib and talazoparib show synthetic lethality in homologous recombination deficient (HRD) cancers including those with BRCA1/2 mutations. Although approved PARPis provide a major therapeutic advance for patients with these cancers, they are associated with hematologic toxicities which limit their therapeutic window and their combinability. All currently approved PARPis non-selectively inhibit PARP1, PARP2 and often additional members of the PARP family. However, inhibition of PARP1 appears to be sufficient for antitumor activity, while PARP2 inhibition is associated with hematologic toxicities in preclinical models. M9466 is a highly potent and selective PARP1 inhibitor with DNA trapping activity. It shows a highly potent antiproliferative efficacy in the DLD-1 (BRCA2 KO) cell line, but not in the DLD-1 wild-type cell line. M9466 exhibited selective antiproliferative activity in a large panel of 96 cancer cell lines in vitro including several BRCA1/2 mutant / PARP-sensitive models. M9466 also selectively inhibited PARP1 vs PARP2 (672-fold) in A549 cells as shown by PARylation inhibition assays after shRNA knockdown of individual PARP genes. M9466 strongly reduced tumor growth in a BRCA1 mutant breast cancer tumor xenograft model in vivo with once daily, oral dosing. To identify top synergistic combination partners for M9466, a large in vitro drug combination screen was conducted with 101 compounds in 35 cancer cell lines. The screen highlighted synergistic activity of M9466 with certain DDR inhibitors (ATR and ATM kinase inhibitors) and with topoisomerase I (Topo I) inhibitors and temozolomide. The combination potential was further evaluated and confirmed in a series of in vivo tumor xenograft studies. Here, M9466 enhanced the antitumor efficacy of the ATR inhibitor tuvusertib and the chemotherapy carboplatin. Thus, M9466 has strong single agent synthetic lethal activity in HRD models and combinability with selected DDRis and chemotherapies. Based on these data, Phase I clinical trials are evaluating M9466-based combinations in patients with advanced solid tumors, and colorectal cancer (NCT06421935, NCT06509906). Citation Format: Heike Dahmen, Ada Sala Hojman, Steffie Revia, Xin Li, Ting Zhang, Nina Berges, Astrid Zimmermann, Thomas Grombacher, Brian Elenbaas. M9466 (HRS-1167): A highly potent and selective PARP1 inhibitor with DNA trapping activity, monotherapy antitumor activity and synergistic potential with DDR inhibitors and chemotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1171.