Abstract ND10: An innovative and reversible WRN helicase inhibitor, GSK4418959 (IDE275), emerges as a promising clinical candidate for MSI-H cancers

Large scale genome wide CRISPR screens identified WRN helicase as a promising synthetic lethal target for MSI-H cancers, independent of tumor type. Here we describe the discovery of the novel clinical WRN helicase inhibitor GSK4418959 (IDE275), which recapitulates the MSI-H synthetic lethality of WRN genetic inhibition in vitro and in vivo. GSK4418959 (IDE275) engages a unique allosteric site in the WRN helicase domain, competing with ATP binding and inducing an inhibitory conformation distinct from previously reported WRN inhibitors. It selectively inhibits the ATPase and DNA unwinding activities of WRN, but not other RecQ helicase family members, including BLM helicase. GSK4418959 (IDE275) binds directly to WRN in cells, inducing DNA damage selectively in MSI-H cancer cells in a concentration-dependent manner. GSK4418959 (IDE275) shows strong anti-proliferative effects in MSI-H cell lines and patient-derived organoids across multiple tumor types with no measurable effects in MSS models. In vivo, GSK4418959 (IDE275) causes tumor regressions and induces DDR markers in several MSI-H CDX and PDX models harboring different oncogenic drivers and tumor suppressor mutations, without affecting MSS models. One of these models was an MSI-H CRC PDX from a patient that had failed 3 previous lines of therapy, including the immune checkpoint inhibitor Nivolumab. Due to its unique binding mode, GSK4418959 (IDE275) also induced regressions in an MSI-H CDX CRC tumor model that had developed resistance to treatment with other reported WRN inhibitors. These findings demonstrate GSK4418959 (IDE275)'s potent and selective preclinical activity against MSI-H cancer models, indicating its potential as a promising clinical treatment for MSI-H cancer patients, including those that have failed existing therapies. All studies were conducted according to GSK's Policy on the Care, Welfare and Treatment of Animals and reviewed by the Institutional Animal Care and Use Committee at GSK or by the ethical review process at the institution where the work was performed. Citation Format: Yanhua Rao, Brian T. Jones, Edward J. Brnardic, Joshua E. Cottom, Yang Lee, Diana M. Munoz, Claire Neilan, Sunjay Sethi, Robert A. Reid, Lisa M. Shewchuk, Ethan D. McSpadden, Daniel L. Severance, Kira Campbell, Philip Landis, Jay Prakash Jain, Richard Zang, Leng Nickels, Dennis J. Murphy, H. Christian Eberl, Muzaffar Alam, Melissa Fleury, Lara K. Leister, Tessa Lynch-Colameta, James P. Phelan, Michael D. VanHeyst, Amberly B. Sanford, Ann M. Rowley, Hongyi Yu, Anna Rutkowska-Klute, Thilo Werner, Xin Linghu, Ian S. Young, An D. Nguyen, Sabrina Bédard, Eldridge N. Nartey, Nanhua Deng, Yang Peng, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Gabriele Picco, Mathew J. Garnett, Jessica L. Schneck, Geeta Sharma, Joshua P. Taygerly, Michael P. DeMartino, Yujiro S. Hata, Paul A. Barsanti, Michael A. White, Benjamin Schwartz. An innovative and reversible WRN helicase inhibitor, GSK4418959 (IDE275), emerges as a promising clinical candidate for MSI-H cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr ND10.