Abstract 233: Preclinical development of EIK1005, a potent and selective inhibitor of Werner helicase.

Abstract The RecQ Werner (WRN) helicase plays a critical role in DNA repair and genomic stability and has been identified as a promising synthetic lethal target in microsatellite instability-high (MSI-H) cancers. Here we present preclinical cellular and in vivo data demonstrating the potent and selective activity of WRN inhibitor EIK1005 across multiple MSI-H cancer models. EIK1005 potently inhibited the biochemical activity of WRN (IC50 = 30 nM), with no activity against BLM and other related RecQ helicases. In MSI-H HCT116 cells, EIK1005 induced DNA damage (EC50 = 90 nM) that correlated with significant anti-proliferative effect (EC50 = 28 nM). Mechanistic studies using our cellular Single Molecule Tracking platform revealed that EIK1005 potently decreased WRN motion, traps WRN on chromatin and promotes WRN degradation, illustrating robust target engagement. No effects of EIK1005 could be measured in microsatellite stable cell lines. EIK1005 has robust pharmaceutical properties including high bioavailability across preclinical species and dose proportional PK. As such, EIK1005 was tested in several mouse models of cancer. In HCT116 xenografted mice, once-daily oral dosing of EIK1005 at 15 and 30 mg/kg induced tumor regression of 48.7% and 47.6%, respectively. In RKO and IGROV-1 MSI-H models that are less sensitive to WRN inhibition, EIK1005 showed dose-dependent tumor growth inhibition across the 30, 90 and 180 mg/kg dose levels assessed. Robust dose-dependent pharmacodynamic activity of EIK1005 was observed in the HCT116 and RKO tumor models, with significant degradation of WRN protein (∼ 70%, 8 h post dosing) observed at 15 and 90 mg/kg EIK1005 dose levels respectively. EIK1005 also mediated consistent elevation of DNA damage response markers in these models. A significant increase in GDF-15 was observed in vitro and in mouse plasma following EIK1005, suggesting GDF-15 elevations as a possible peripheral biomarker of WRN inhibition. The pharmacodynamic changes observed at the 15 and 90 mg/kg dose levels correlated with robust and dose responsive plasma concentrations. Further studies elucidated several mechanisms of potential resistance to WRN inhibition. Overall, our preclinical characterization of EIK1005 demonstrates its strong activity and favorable pharmacologic profile that provide impetus to the ongoing clinical development of EIK1005 in patients with MSI-H cancers. Citation Format: Fernando Rodriguez Perez, Danny Murnock, Juanita Ezemba, Tamer Ahmed, Jose Ortega, Huntly M. Morrison, Rafael Miranda, Taylor Heuer, Stephen Jones, Brenda Smith, Ali Tabatabaei, Stephen Basham, Melissa Dumble, Marcus P. Kelly. Preclinical development of EIK1005, a potent and selective inhibitor of Werner helicase [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 233.