Abstract B020: Preclinical assessment of WRN inhibitor HS-10515 for selective targeting of MSI-H cancers

Abstract Microsatellite instability-high (MSI-H) is a genetic hallmark present in a subset of malignancies, including colorectal, endometrial, and gastric cancers, arising from deficiencies in the DNA mismatch repair (MMR) system. Although MSI-H tumors often respond to immune checkpoint inhibitors, approximately 30–50% of patients show limited or no clinical benefit, highlighting the need for alternative therapeutic strategies. Werner Syndrome Helicase (WRN), a RecQ family helicase critical for genome maintenance, has been identified as a synthetic lethal target in MSI-H cancers. In this study, we describe the preclinical profiling of two potent, and selective WRN inhibitors—HS-10515 and HBC-00015875. HS-10515 demonstrated robust inhibition of WRN activity and induced strong anti-proliferative effects in a panel of MSI-H cancer cell lines derived from colorectal, endometrial, and gastric tumors. Both compounds exhibit favorable drug-like properties, including excellent pharmacokinetic (PK) profiles, significant tumor growth inhibition, with pharmacodynamic (PD) biomarker induction and WRN degradation closely correlating with efficacy, supporting their advancement into clinical development. Citation Format: Tzu-Pei Chang, Gang Liu, Sangwoo Cho, Lingtian Zhang, Xinlin Du, Shuwen He, Robert Yang, Lance Lee. Preclinical assessment of WRN inhibitor HS-10515 for selective targeting of MSI-H cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B020.