Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• WNT signaling is crucial in cancer development, especially colon cancer, and drives cancer stem cell maintenance.
• Dysregulation of WNT signaling is a common hallmark of various malignancies.

Purpose of the Study:

• To discover and optimize novel small-molecule inhibitors of WNT signaling.
• To develop potent WNT pathway inhibitors with favorable pharmacokinetic properties for potential cancer therapy.

Main Methods:

• High-throughput cell-based reporter assay to screen for WNT pathway modulators.
• Structure-activity relationship studies and medicinal chemistry optimization of a pyridine scaffold.
• X-ray crystallography to determine the compound's conformation.
• In vivo studies using human tumor xenograft models to assess efficacy and pharmacokinetics.

Main Results:

• Discovery of a 3,4,5-trisubstituted pyridine derivative (compound 9) with WNT pathway inhibitory activity.
• Optimization led to CCT251545, a potent WNT signaling inhibitor with a specific twisted conformation and good oral bioavailability.
• Demonstrated inhibition of WNT pathway activity and significant tumor growth inhibition in a human tumor xenograft model after oral administration.

Conclusions:

• Successful hypothesis-driven optimization of a WNT signaling inhibitor from a cell-based assay hit.
• CCT251545 represents a promising WNT signaling inhibitor for preclinical development in cancers driven by WNT pathway dysregulation.
• This study highlights the potential of targeting WNT signaling in cancer therapy.