Allosteric inhibitor of ?-catenin selectively targets oncogenic Wnt signaling in colon cancer.

ABSTRACT: Abnormal regulation of ?-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, ?-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel ?-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of ?-catenin. C2 selectively inhibits ?-catenin, lowers its cellular load and significantly reduces viability of ?-catenin-driven cancer cells. Through direct binding to ?-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of ?-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of ?-catenin.

SUBMITTER: Cheltsov A 

PROVIDER: S-EPMC7229215 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature