Abstract 4192: Preclinical characterization of LAE122, a novel, potent and selective WRN inhibitor for the treatment of MSI-H tumors

Abstract DNA mismatch repair (dMMR) deficiency could induce damage of genome, resulting Microsatellite instability (MSI-H), which is frequently observed in various tumor types, including colorectal, gastric, endometrial, and ovarian cancers. Although immune checkpoint inhibitors (ICI) have been approved for the treatment of MSI-H tumors, significant unmet medical need remains across several tumor types that fail to respond or relapse with ICI therapies. Werner syndrome ATP-dependent helicase (WRN) is a RecQ family helicase that plays important roles in DNA repair and in the maintenance of genome integrity. Recent studies have identified WRN as a promising synthetic lethal drug target for MSI-H cancers. LAE122 is a novel, potent and selective WRN inhibitor developed by Laekna through structure-based drug design strategy. LAE122 has highly differentiated structure from bench-mark molecules and displayed single digit nanomolar IC50 values in biochemical assay and cell anti-proliferation assay on MSI-H cells but had no effect on Microsatellite stability (MSS) cells up to 10 µM. LAE122 demonstrated favorable drug-like properties, including good in vitro ADMET and in vivo PK with low plasma clearance and high oral bioavailability across animal species. In SW48 and HCT116 CDX models, LAE122 showed robust anti-tumor growth effect at lower doses than bench-mark molecules with strong evidence on biomarker change. LAE122 didn’t have off-target liability in in vitro assays and demonstrated good tolerability in preclinical toxicology studies. In conclusion, LAE122 is a novel, potent and selective WRN inhibitor for the treatment of MSI-H tumors. Citation Format: Ming Li, Minhua Zhang, Junyan Chen, Chaojun Cai, Xiaofen Lin, Justin Gu. Preclinical characterization of LAE122, a novel, potent and selective WRN inhibitor for the treatment of MSI-H tumors [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 4192.