Taking the road less traveled – the therapeutic potential of CBP/β-catenin antagonists

ABSTRACT

Successfully targeting aberrant Wnt signaling in cancer, and even more so in chronic diseases, requires a fine balancing act, wherein the ‘dark side’ of Wnt signaling in disease can be abrogated without interfering with the crucial roles of Wnt signaling in normal tissue homeostasis and repair. Our identification of small molecule CBP/β-Catenin antagonists revealed (a) the distinctive roles that the Kat3 coactivators CBP and p300 play in Wnt signaling and orchestrating critical cellular decisions, and (b) their therapeutic potential.

Areas covered

This perspective discusses the challenges of targeting the Wnt signaling cascade, the safety, efficacy, and therapeutic potential of specific CBP/β-catenin antagonists and a rationale for the pleiotropic effects of CBP/β-catenin antagonists beyond Wnt signaling.

Expert opinion

CBP/β-catenin antagonists can correct lineage infidelity, enhance wound healing, both normal and aberrant (e.g. fibrosis) and force the differentiation and lineage commitment of stem cells and cancer stem cells by regulating enhancer and super-enhancer coactivator occupancy. Small molecule CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin versus p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging, via maintenance of our somatic stem cell pool, and regulating mitochondrial function and metabolism involved in differentiation and immune cell function.

KEYWORDS:

• CBP
• p300
• CBP/β-catenin antagonist
• somatic stem cell
• cancer stem cell
• metabolism
• enhancer
• super-enhancer

ARTICLE HIGHLIGHTS

• Successfully selective targeting of aberrant Wnt signaling in cancer, and even more so in chronic diseases, requires a fine balancing act, wherein the ‘dark side’ of Wnt signaling in disease can be abrogated without interfering with the crucial roles of Wnt signaling in normal tissue homeostasis and repair.

• The identification of small molecule CBP/β-Catenin antagonists revealed (a) the distinctive roles that the Kat3 coactivators CBP and p300 play in Wnt signaling and orchestrating critical cellular decisions, and (b) their therapeutic potential.

• Although further development and additional clinical studies are needed, it appears that CBP/β-catenin antagonists, while not specifically affecting the Wnt pathway alone, and more generally regulating a fundamental evolutionary control mechanism, may be able to safely target the ‘Wnt pathway’ for the treatment of multiple disease indications.

• With the discovery of new, potent, specific and orally available CBP/β-catenin antagonists, perhaps we will finally definitively demonstrate that ‘We Can Safely Target The Wnt Pathway.’

This box summarizes key points contained in the article.

Acknowledgments

The author would like to acknowledge Barry Davison, Ph.D. for reading, critiquing and providing constructive comments on the manuscript. The author would also like to acknowledge Jia-Ling Teo, City of Hope, Beckman Research Institute, for reading, critiquing and providing constructive comments of the manuscript, as well as assisting with putting the figures together.

Declaration of Interests

Michael Kahn, Ph.D. has an equity position in [3+2]-Pharma. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Support from the City of Hope Comprehensive Cancer Center Support Grant NIH P30CA033572, NIH R01CA166161, R21NS074392, R21AI105057, R01HL112638 and the Rotary Coins for Alzheimer’s Research Trust (CART) is gratefully acknowledged.