Abstract LB187: YF087 is a potent and selective inhibitor of WRN, specifically targeting MSI-H cancer cells

Abstract The impairment of DNA mismatch repair (MMR) function occurs in various cancers, including colorectal (15%), gastric (22%), endometrial (20-30%) and ovarian (10-15%) cancers. MMR-deficient (dMMR) cancers are characterized by a high mutational load and frequent insertion and/or deletion events in repetitive DNA sequences, a condition known as microsatellite instability-high (MSI-H). The Werner syndrome protein (WRN) is essential for the survival of cancer cells exhibiting microsatellite instability (MSI) and represents a synthetic lethal target for MSI-H/dMMR cancers. We have identified YF087, a highly selective, reversible and potent WRN inhibitor that has demonstrated robust activity in both in vitro anti-proliferation assays and in vivo cancer xenograft models. YF087 exhibited an IC50 of 8.1 nM in the WRN helicase enzymatic assay and an IC50 of 42 nM in the anti-proliferation assay in SW48 (MSI-H) colorectal cancer cell. YF087 exhibits excellent selectivity against another helicase BLM at the enzymatic level and is highly selective for MSI-H cells compared to microsatellite stable (MSS) cell in the anti-proliferation assay. YF087 is more effective than both WRN reversible inhibitor HRO761 and irreversible inhibitor RG6457 in the SW48 cellular anti-proliferation assay in the presence of 50% human serum. In the HCT116 colorectal cancer xenograft model, 5 mg/kg, 15 mg/kg and 45 mg/kg YF087 oral and daily treatment for 22 days induced regression rates of 32%, 43% and 57%, respectively. Tumors continue to regress after the treatment ends and remained tumor-free status for more than two months after dose termination at the 45 mg/kg dose. YF087 also exhibits superior in vivo anti-tumor efficacy in other MSI-H/dMMR cancer xenograft models upon oral and daily treatment and maintained longer tumor regression after termination of treatment vs HRO761 and RG6457. In patient derived MSI-H gastrointestinal cancer models resistant to anti-PD-1 therapy, treatment with YF087 resulted in tumor inhibition or regression. YF087 also possesses favorable preclinical ADME profiles suitable for clinical development. Based on these findings, YF087 is currently in IND-enabling studies to support phase 1 clinical trial in MSI-H/dMMR cancer patients. Citation Format: Yaolin Wang, Rongfeng Liu, Yanxin Yu, Hong Yang, Jifang Weng, Yan Weng, Hong Mei, David Dai. YF087 is a potent and selective inhibitor of WRN, specifically targeting MSI-H cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB187.