Specific Direct Small Molecule p300/β-Catenin Antagonists Maintain Stem Cell Potency.

Area of Science:

• Molecular Biology
• Biochemistry
• Stem Cell Biology

Background:

• CBP and p300 are homologous Kat3 transcriptional coactivators with distinct roles in signaling.
• The Wnt/β-catenin pathway is critical in development and disease.
• ICG-001 selectively inhibits CBP/β-catenin, but a p300 antagonist was lacking.

Purpose of the Study:

• To identify and validate the first direct antagonists of the p300/β-catenin interaction.
• To explore the role of p300/β-catenin antagonism in maintaining embryonic stem cell (ESC) pluripotency.

Main Methods:

• Chemical screening to identify specific p300/β-catenin antagonists.
• Validation of antagonist activity through biochemical and cellular assays.
• Assessment of the effect of antagonists on ESC pluripotency.

Main Results:

• Identification and validation of YH249/250 as highly specific, direct p300/β-catenin antagonists.
• YH249/250 were shown to maintain pluripotency in ESCs.
• These compounds represent novel chemical tools for studying p300-mediated transcription.

Conclusions:

• YH249/250 are the first direct antagonists of p300/β-catenin interactions.
• These antagonists can maintain ESC pluripotency, highlighting the importance of the p300/β-catenin axis.
• This discovery provides new avenues for therapeutic strategies involving the Wnt pathway.