Abstract 4525: Discovery of a highly potent and selective PARP1 inhibitor with superior PK and safety profiles

Abstract PARP inhibitors have been an effective treatment option for cancers deficient in homologous recombination repair, such as ovarian, breast, prostate, and pancreatic cancers, particularly those harboring BRCA mutations. However, their severe overlapping hematological and gastrointestinal toxicities have limited their clinical use, especially in the combination therapies with other anti-cancer agents. More recently, studies have shown that inhibiting PARP1 mainly drives anti-tumor activity while inhibiting PARP2 contributes to the hematological toxicity such as anemia due to its essential role in the survival of hematopoietic stem and progenitor cells. Thus, there is an urgent need for developing a selective PARP1 inhibitor. In this study, we report the discovery and characterization of a unique PARP1 inhibitor, ACE-86225106. This molecule is highly selective at inhibiting PARP1 over PARP2 as demonstrated in biochemical (72x) and DNA-trapping (131x) assays. It demonstrates potent anti-proliferative activities against BRCA mutant cancer cell lines (IC50 = 1-9 nM) but not against BRCA wild type cancer cells (IC50 30, 000 nM). As compared to the BRCA mutant cancer cells, this molecule is much less active at inhibiting the differentiation of CD34+ hematopoietic stem cells (IC50 ≈ 450-1, 400 nM), i. e.: erythroid, myeloid and megakaryocyte. The results of these studies show that ACE-86225106 is a highly potent and selective PARP1 inhibitor. This molecule has a unique PK profile characterized by its long half-life and low volume of distribution. As such, it demonstrates robust efficacy at low dose (1 mg/kg) with a less frequent dosing schedule (once a week). Importantly, there was no significant body weight loss observed in the treatment group even at much higher doses (10 mg/kg), but there was a significant body weight gain. The GLP toxicology studies have confirmed its superior safety profile as the maximum recommended safe starting first-in-human dose was 5-fold higher than the predicted human efficacious dose. Taken together, ACE-86225106 is a highly potent, selective PARP1 inhibitor with excellent PK and safety profile and expected to have a better safety profile, deeper and more durable clinical responses, and broader utility in the clinic as a preferred combination partner with other anti-cancer therapies. A phase 1 clinical trial to evaluate its safety, PK, and clinical utility is to begin in early 2024. Citation Format: Yi Wei, Wenming Li, Zehui Li, Manhua Li, Kai Kang, Zhiming Wen, Tinggui Yin, Kuo-Long Yu, Genshi Zhao, Hongbin Yuan. Discovery of a highly potent and selective PARP1 inhibitor with superior PK and safety profiles abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4525.