Characterization of ARTS-051, a potent and selective Werner helicase inhibitor effective against a broad range of MSI-H colorectal cancer models

Microsatellite instability, caused by defects in DNA mismatch repair, is a feature of many cancers including colorectal, gastric, endometrial, and ovarian. Werner helicase (WRN), a RecQ helicase involved in genome maintenance and DNA damage repair, is essential for cancer cells with high microsatellite instability (MSI-H), making it a promising target for the treatment of MSI-H cancers. Here we characterize a new non-covalent WRN inhibitor, ARTS-051, which is potent and selective across multiple MSI-H colorectal cancer models. In enzymatic assays, ARTS-051 inhibits WRN ATPase and helicase activity and displays over 2000-fold selectivity for WRN over the most closely related RecQ helicase, BLM. ARTS-051 also demonstrates excellent potency against the proliferation of both highly sensitive MSI-H cell lines (HCT116 and SW48) and less sensitive MSI-H cell lines (SNU-407 and RKO). At the same time, ARTS-051 exhibits more than 90-fold selectivity over microsatellite stable (MSS) cell line HT29. Mutation of WRN C727 confers resistance to existing WRN inhibitors, making it a potential vulnerability of these inhibitors. In contrast, ARTS-051 is effective in WRN C727S and C727A mutant HCT116 cells, outperforming the clinical stage WRN inhibitor HRO761 by nearly 10-fold. In multiple MSI-H cell-line derived mouse models including the less sensitive RKO and mutant WRN C727S HCT116 models, treatment with ARTS-051 leads to tumor regression without significant toxicity. Additionally, ARTS-051 displays good drug-like properties including solubility, permeability, and liver microsome stability, as well as a positive PK profile with low clearance and good oral exposure across species, supporting favorable clinical dose projections. Taken together, these data show that ARTS-051 is a promising WRN inhibitor with best-in-class potential to treat MSI-H colorectal cancers.