Abstract 1755: Discovery of a novel, selective WRN inhibitor, DAT-5000A, in the treatment of microsatellite-unstable tumors

Abstract Werner syndrome ATP-dependent helicase (WRN) is a member of RecQ helicase involved in DNA replication and repair and is identified as a synthetic lethal target in microsatellite instability-high (MSI-H) tumors. MSI-H feature has been found in a variety of tumor types including colorectal, gastric and endometrial cancers. The clinical benefits of immune checkpoint inhibitor (ICI) such as anti-PD-1 or anti-PD-L1 antibodies on MSI-H cancers have been well documented; however, nearly 20-50% of these cancer patients are intrinsically resistant to PD-(L)1 therapies or develop acquired resistance with prolonged treatment. Thus, agents targeting MSI-H tumors are of great interest. Here we described the discovery of a novel non-covalent WRN inhibitor, DAT-5000A, with excellent potency and PK profile. DAT-5000A potently inhibited WRN in vitro activity both on ATPase and unwinding assays and showed good selectivity over BLM, another member of RecQ helicase. DAT-5000A also showed selective killing of MSI-H SW48 but not MSS (microsatellite stability) SW620 tumor cell line. In addition, DAT-5000A demonstrated good drug-like properties including high cell permeability and microsomal metabolic stability, as well as favorable PK profile with low in vivo clearance and optimal oral bioavailability, across multiple species. DAT-5000A exhibited single-agent activity with tumor regression on MSI-H cell-line derived xenograft (CDX) tumor models, meanwhile DAT-5000A did not cause any abnormality on these mice. Our data demonstrated that DAT5000A is a potent, selective WRN inhibitor with sufficient in vivo exposure and acceptable preliminary safety profile, which supports DAT-5000A to be further evaluated in human clinical trials. Citation Format: Jingxi Zhang, Huixian Chen, Dan Yan, Xi Chen, Jincong Zhuo, Kevin Zhou. Discovery of a novel, selective WRN inhibitor, DAT-5000A, in the treatment of microsatellite-unstable 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 1755.