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

Abnormal regulation of beta -catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, beta -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 beta -catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of beta -catenin. C2 selectively inhibits beta -catenin, lowers its cellular load and significantly reduces viability of beta -catenin-driven cancer cells. Through direct binding to beta -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 beta -catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of beta -catenin.