Abstract 412: Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth

Abstract Loss of function mutations in DNA mismatch repair genes can result in microsatellite instabilities (MSI) and high levels of MSI (MSI-H) contributes to tumorigenesis and is frequently observed in endometrial carcinoma, gastric cancer, and colorectal cancer. Although immune checkpoint inhibitors have been approved for the treatment of MSI-H tumors, there is still a large proportion of patients with MSI-H tumors who fail to respond to these therapies. Recently, two independent genome-wide loss of function screens have identified Werner syndrome helicase (WRN) as the top dependency for MSI-H cancer cell viability. WRN plays important roles in DNA repair and in the maintenance of genome integrity. Given that WRN deficiency selectively impairs the viability of MSI-H but not microsatellite stable cancer cells, WRN is a synthetic lethal target for MSI-H tumors. ISM9342A is a novel and potent WRN inhibitor exhibiting single digit nanomolar IC50 values in both ATPase and helicase assays. ISM9342A suppressed the proliferation and increased double strand break markers in MSI-H cancer cells. Moreover, ISM9342A demonstrated promising in vivo anti-tumor efficacy in an MSI-H xenograft model along with tumor regression. ISM9342A demonstrated good drug-like properties, including excellent in vitro ADMET profiles and good in vivo exposure, including low clearance and optimal oral bioavailability across multiple preclinical species. Collectively, these findings highlight the potential of ISM9342A as a highly potent WRN inhibitor for the treatment of MSI-H tumors Citation Format: Pei Zhao, Wei Zhu, Xiaoyu Ding, Jianfei Wan, Xiaojing Chen, Man Zhang, Xiao Ding, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov. Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth 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 412.