Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors

Abstract PARP1/2 inhibitors are FDA approved for treatment of cancers such as ovarian, prostate, pancreas and breast with greatest activity against tumors harboring BRCA1 or 2 mutation or homologous recombination deficiency (HRD). A shared adverse event that contributes to a narrow therapeutic index and limits combination potential is hematologic toxicity. First generation PARP inhibitors are not selective against PARP2, which has been shown to play a role in the survival of hematopoietic progenitor cells in animal models. However genetic studies suggest that the synthetic lethality from PARP trapping with HRD is primarily dependent on PARP1. We hypothesized that a potent and selective PARP1 inhibitor and trapper would achieve equivalent anti-tumor activity as non-selective PARP inhibitors while alleviating toxicities caused by PARP2 inhibition. SNV-001 is a novel, proprietary, potent, and selective PARP1 inhibitor and trapper. In PARylation assays, SNV-001 inhibited PARP1 activity with low nanomolar potency and displayed greater than 500-fold selectivity against PARP2. In cellular PARP trapping assays, SNV-001 potently trapped PARP1 on DNA in a dose-dependent manner but did not trap PARP2 up to 25 µM. Functionally, SNV-001 exhibited selective growth inhibitory activity against cancer cell lines with impaired HR function. In anti-proliferation and colony formation assays of BRCA-mutant cell lines including MDA-MB-436 (BRCA1 deficient) and DLD1 (BRCA2 knockout), SNV-001 inhibited cell growth and colony formation with single-digit nM IC50 values while having minimal effects against BRCA-WT cells. In a subcutaneous MDA-MB-436 xenograft tumor model, SNV-001 administered orally once daily achieved dose-dependent inhibition of PARylation in vivo. Furthermore, SNV-001 showed dose-dependent tumor growth inhibition using low daily doses with greater efficacy compared to olaparib dosed at 100 mg/kg once daily. In the cohort receiving a higher dose of SNV-001, all animals showed complete regression after 35 days of treatment without any clinical signs of toxicity. In summary, we have discovered SNV-001, a potent and selective PARP1 inhibitor and trapper that shows excellent activity against cancer models with HRD in vitro and in vivo. These data support advancement of SNV-001 into clinical development for patients with tumors characterized by HRD. Citation Format: Mingming Gao, Zhentian Li, Qipeng Fan, Jun Pan, Yu Bai, Hewen Zhang, Yu Li, Yongzhong Wu, Phillip C.C. Liu, Liangxing Wu, Wenqing Yao, Hui Wang. Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1648.