2020-371 WNT-B-CATENIN SIGNALING PATHWAY INHIBITORS

UCLA researchers from the Department of Pediatrics have uncovered a novel inhibitor to the Wnt/β-catenin signaling pathway.

BACKGROUND:

Airways in the throat play a vital role in host defense to protect mammals from airborne pathogens. This protective effect is accomplished by a specialized type of epithelium, the mucocillary epithelium, that comes from adult airway basal stem cells (ABSCs). When cells in the airway are wounded, signaling through the Wnt/β-catenin pathway is crucial for ABSC cells to proliferate and then differentiate into mucocillary epithelial cells. If the Wnt/β-catenin signaling pathway is dysregulated, the ABSC cells hyper-proliferate and do not properly form mucocillary epithelial cells. Dysregulated repair can lead to various pathologies, including ABSC hyperplasia and stepwise progression to squamous lung cancer. Methods to prevent the dysregulation of this pathway remain elusive.

INNOVATION:

UCLA researchers conducted a high-throughput drug screen for inhibitors of the Wnt/β-catenin signaling pathway. They uncovered a compound named Wnt Inhibitor Compound 1 (WIC1). The molecule was applied to an in vitro model of ABSC hyperproliferation and was able to reverse the hyperproliferation process and promote ciliated cell differentiation. WIC1 remained nontoxic even at concentrations as high as 10 M.

POTENTIAL APPLICATIONS:

• Promote normal airway repair after injury, such as smoke inhalation or a viral infection

• Treatment of pulmonary diseases such as Chronic Obstructive Pulmonary Disease (COPD)

• Research tool for Wnt/B-catenin signaling

ADVANTAGES:

• Suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity

• Reduces ABSC proliferation

• Induces ciliated cell differentiation

• Decreases nuclear p-β-cateninY489

DEVELOPMENT-TO-DATE:

The inhibitor was screened on mouse ABSC and human ABSC cell lines.