Abstract 2913: Preclinical characterization of GSK4418959 (IDE275): A potent, selective, and highly efficacious WRN inhibitor for MSI-H tumors across multiple cancer types

Large-scale genome-wide CRISPR screens have identified WRN helicase, RecQ family, as a promising synthetic lethal target for microsatellite instability-high (MSI-H) cancers across tumor types. GSK4418959 (IDE275) was discovered as a novel WRN helicase inhibitor to treat MSI-H cancer. Here, we present the cellular and in vivo evidence to demonstrate the selectivity and efficacy of GSK4418959 (IDE275) in multiple MSI-H models across various solid tumor types, including colorectal (CRC), endometrial, and gastric cancers. GSK4418959 (IDE275) demonstrates potent anti-proliferative effects in MSI-H cancer cell lines and patient-derived organoids across multiple tumor types, with no measurable impact on microsatellite-stable (MSS) models. In vivo, GSK4418959 (IDE275) induces tumor regression and activates DNA damage response (DDR) markers in several MSI-H CDX and PDX models across diverse tumor types, including CRC, endometrial, and gastric cancers with varying oncogenic drivers and tumor suppressor mutations, while sparing MSS models. One notable model is an MSI-H CRC PDX derived from a patient who had failed three prior lines of therapy, including the immune checkpoint inhibitor Nivolumab. With its unique binding mode, GSK4418959 (IDE275) showed tumor regression in an MSI-H CRC CDX model resistant to other existing WRN inhibitors. Additionally, GSK4418959 (IDE275) showed efficacy in chemotherapy-refractory MSI-H, HER2-negative gastric cancer patient-derived models. Furthermore, GSK4418959 (IDE275) also demonstrated combinatorial effects with existing standard-of-care therapies to benefit MSI-H cancer patients. These findings underscore GSK4418959 (IDE275)’s potency and highly selective activity against MSI-H cancer models in preclinic, highlighting its potential as a promising treatment option for MSI-H cancer patients in clinical setting, both as in monotherapy for those unresponsive to current cancer treatments and in combination with existing therapies for enhanced clinical benefit. 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: Yang Lee, Phil Landis, Nanhua Deng, Diana Munoz, Jay Prakash Jain, Brian T. Jones, Edward J. Brnardic, Joshua Cottom, Jianxia Shi, Youyou Zhang, Robert Silvers, Xin Linghu, Ian Young, Yang Peng, Dawin Khiev, Gabriele Picco, Mathew Garnett, Joshua Taygerly, Mike P. DeMartino, Claire Neilan, Paul Barsanti, Michael White, Gul Y. Serbest, Yanhua Rao, Benjamin Schwartz, Geeta Sharma. Preclinical characterization of GSK4418959 (IDE275): A potent, selective, and highly efficacious WRN inhibitor for MSI-H tumors across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2913.