Abstract 4519: FS-207: A potential best-in-class WRN helicase inhibitor for treating MSI-H cancers.

Abstract Microsatellite instability-high (MSI-H) cancers, characterized by impaired DNA mismatch repair (MMR), are vulnerable to synthetic lethal targeting of Werner Syndrome RecQ helicase (WRN). Although PD-1 inhibitors are the standard treatment for MSI-H tumors, their response rate is around 40%-60%, with many patients eventually developing resistance and relapse. WRN inhibition offers a promising alternative therapeutic strategy, potentially overcoming resistance to PD-1 inhibitors. We discovered FS-207, a potent and selective small-molecule inhibitor of WRN helicase, using Foresight Therapeutics' multimodal drug discovery platform. FS-207 demonstrates low nanomolar potency in inhibiting WRN helicase/ATPase activity and exhibits over 1000-fold selectivity against other RecQ helicases. Inhibition of WRN by FS-207 induces chromosomal structure aberrances, leading to selective killing of MSI-H cancer cells via the DNA damage response pathway. FS-207 is well tolerated, with excellent pharmacokinetic properties. Its potent inhibition of WRN helicase, combined with favorable oral bioavailability, translates into robust and durable efficacy in MSI-H cancer cell line derived (CDX) and patient-derived (PDX) xenograft models. Notably, tumor regression was observed in mice dosed at 5 mg/kg or higher in these models. Study results, including efficacy and pharmacodynamic responses, will be presented. Our findings position FS-207 as a promising, potentially best-in-class WRN helicase inhibitor for the treatment of MSI-H cancers, owing to its superior efficacy, durability, and selectivity. FS-207 is poised to enter clinical trials in 2026. Citation Format: Bin Li, Cai Wu, Yaqian Liu, Linsen Li, Yan Ma, Dongbo Li. FS-207: A potential best-in-class WRN helicase inhibitor for treating MSI-H cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4519.