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

  • Sci Rep. 2020 May 15;10(1):8096. doi: 10.1038/s41598-020-60784-y.
Anton Cheltsov  1 ,  Natsuko Nomura  2 ,  Venkata M Yenugonda  2 ,  Jatin Roper  3 ,  Rajesh Mukthavaram  4 ,  Pengfei Jiang  4 ,  Nam-Gu Her  5 ,  Ivan Babic  2 ,  Santosh Kesari  2 ,  Elmar Nurmemmedov  6
Affiliations
  • 1. Q-MOL LLC, San Diego, California, United States of America.
  • 2. John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
  • 3. Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina, 27710, USA.
  • 4. Translational Neuro-Oncology Laboratories, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • 5. Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Seoul, 01812, Korea.
  • 6. John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. [email protected].
PMID: 32415084 DOI: 10.1038/s41598-020-60784-y
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.

Products