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

Publication Title

Sci Rep

Authors

Anton Cheltsov
Natsuko Nomura, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.Follow
Venkata Mahidhar Yenugonda, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.Follow
Jatin Roper
Rajesh Mukthavaram
Pengfei Jiang
Nam-Gu Her
Ivan Babic, John Wayne Cancer Institute & Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.Follow
Santosh Kesari, Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USAFollow
Elmar Nurmemmedov, John Wayne Cancer Institute & Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.Follow

Document Type

Article

Publication Date

5-15-2020

Abstract

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

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology