Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers

Abstract

The Werner protein, WRN, is a member of the RecQ helicase family implicated in genome maintenance. Several large-scale functional genomics screens have identified WRN as a synthetic lethal target in cancer cell lines with microsatellite instability-high (MSI-H). Accordingly, WRN is considered a potential therapeutic target in MSI-H cancers. HRO761, a non-covalent WRN inhibitor developed by Novartis, entered clinical trial for patients with MSI-H colorectal cancer (CRC). In this study, we investigated bioisosteric replacement of the hydroxyl pyrimidine residue of HRO761 with several bicyclic structures to obtain a novel chemical entity. In vitro ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an in vivo study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle.

Keywords: Colorectal cancer; HRO761; MSI-H; WRN; WRN inhibitor.