Abstract 5725: The potent and selective PARP1 inhibitor and trapper SNV1521 exhibits combination activity with targeted and chemotherapeutics

SNV1521 is clinical stage PARP1 inhibitor and trapper with excellent potency and selectivity against other MARP and PARP proteins. Although several first generation non-PARP1 selective inhibitors have been approved primarily as monotherapy for BRCA-associated tumors, they have not fully realized the potential of PARP inhibition as a mechanism for potentiation of chemo-, DNA damage response, and radiation therapy because of overlapping toxicities including hematologic suppression. SNV1521 shows exquisite selectivity for PARP1 over PARP2 and other related proteins in biochemical assays compared with both first-generation PARPi and saruparib. In colony formation assays using normal donor HSPCs, SNV1521 exhibited significantly less suppression of the proliferation of both myeloid and erythroid lineages compared with these inhibitors. When comparing with the target efficacious concentration using a BRCA2-deficient cell line versus the NOEL for suppression of heme progenitors, SNV1521 showed an expanded margin versus either olaparib or saruparib. These data support the potential of SNV1521 to combine more effectively with approved and experimental oncology drugs. In cell-based combination experiments, SNV1521 strongly synergized with topoisomerase-1 inhibitors as well ADCs utilizing topo-1 based warheads. Importantly, the combination benefit extended to cell lines that were not intrinsically sensitive to PARP inhibitors suggesting activity in cell models beyond those with functional defects in homologous recombination. In a PDX model of breast cancer, the combination of topotecan with SNV1521 showed deeper tumor regression than either agent alone. Moreover, this activity showed durable anti-tumor activity after cessation of dosing. In summary, these data support the continued clinical development of SNV1521 as monotherapy and also in combination with drugs that are mechanistically synergistic but cannot be effectively combined with less selective PARP1 inhibitors because of overlapping toxicities. Citation Format: Mingming Gao, Qipeng Fan, Zhentian Li, Jun Pan, Renxu Chang, Liangxing Wu, Wenqing Yao, Phillip CC Liu. The potent and selective PARP1 inhibitor and trapper SNV1521 exhibits combination activity with targeted and chemotherapeutics [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 5725.