CBP/β-catenin Antagonists: A Safe and Novel Approach for Skin Rejuvenation and Aging

Long-lived somatic stem cells regenerate adult tissues throughout our lifetime. However, with aging, there is a significant deterioration in the function of stem cells, which contributes to decreased tissue regeneration. The decision for a long-lived somatic stem cell to become activated and subsequently to undergo either a symmetric or an asymmetric division is a critical cellular decision process.

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Wnt/β-catenin signaling regulates various cellular processes, including proliferation, differentiation, and tissue organization and development. Based upon work done primarily in Michael Kahn’s laboratory over the past 25 years, we have discovered that differential usage by β-catenin of the highly similar Kat3 coactivators CREB-binding protein (CBP) and p300 is critical in somatic stem cell activation and the regulation of symmetric versus asymmetric divisions.

CBP/β-catenin antagonists are small molecule compounds that inhibit the disrupt the interaction between CBP and β-catenin thereby enhancing the p300/β-catenin interaction. This antagonistic effect in somatic stem cells induces activation and initiates a differentiative program to regenerate tissue. Among other indications investigated both pre-clinically and clinically, CBP/β-catenin antagonists have emerged as a novel approach to enhance skin rejuvenation and addressing the signs of skin aging.¹

Wnt/β-catenin signaling plays a crucial role in skin development, homeostasis, regeneration, and aging. Below, is an overview of the top 5 considerations to show how CBP/β-catenin antagonists can be utilized for skin rejuvenation and anti-aging by enhancing Wnt/p300/β-catenin transcription:
1. Inhibition of collagen degradation: With age, the activity of matrix metalloproteinases (MMPs) increases, leading to the degradation of collagen, a key component of the skin's structure and elasticity. CBP/β-catenin antagonists can inhibit the expression and activity of MMPs, thereby reducing collagen breakdown and preserving the skin's firmness and elasticity.
2. Stimulation of collagen synthesis: CBP/β-catenin antagonists can also promote collagen synthesis in the skin. They can activate fibroblasts, the cells responsible for producing collagen, and stimulate the production of new collagen fibers. This helps to improve skin texture, smoothness, and reduce the appearance of wrinkles and fine lines.
3. Enhancement of epidermal regeneration: The Wnt/β-catenin signaling pathway is involved in regulating epidermal cell proliferation and differentiation. CBP/β-catenin antagonists can modulate this pathway to promote the regeneration of the epidermis via the activation of epidermal stem cells, leading to a more youthful and rejuvenated skin appearance.
4. Reduction of pigmentation irregularities: Dysregulation of the Wnt/β-catenin pathway can contribute to abnormal pigmentation, such as age spots and uneven skin tone. CBP/β-catenin antagonists can help regulate melanin production and distribution, leading to a more even and balanced skin pigmentation.
5. Anti-inflammatory effects: Chronic inflammation is associated with skin aging. CBP/β-catenin antagonists can help reduce inflammation in the skin by enhancing the skins barrier function, thereby inhibiting the activation of pro-inflammatory mediators. This can help alleviate redness, irritation, and other signs of inflammation associated with aging.

In 2023, the USPTO issued Genesis Molecular Technologies Inc. a patent on new compositions of matter for proprietary CBP/β-catenin antagonists. The patent (No: US 11,639,356 B2) relates generally to modulation of the Wnt/β-catenin pathway in mammalian cells and tissues, and more specifically to novel CREB binding protein (CBP)/β-catenin inhibitors and the cosmetic, and therapeutic uses thereof (eg, in dermatological applications for skin, hair and nails), and methods for making the disclosed exemplary compounds.²

βSTEM6, a specific CBP/β-catenin antagonist has the unique ability to induce asymmetric differentiation of stem cells to regenerate new tissue. The synthesis of the βSTEM6 molecule was initiated by Fuqiang Ruan PhD, and required several years of discovery and refinement.

An 8-week clinical study and a biopsy sub-study was conducted on βSTEM6 by Zoe Draelos, MD, of Dermatology Consulting Services, PLLC, in High Point, North Carolina. The findings demonstrate the strong anti-aging performance with 8 weeks of use. Moreover, a gene expression study was conducted on human skin treated either with vehicle or βSTEM6 with statistically significant changes (p< 0.05).³

It's important to note that the use of CBP/β-catenin antagonists for skin rejuvenation and aging is still an emerging field, and further research is needed to fully understand their efficacy. Clinical trials and studies are ongoing to explore the potential of these antagonists as novel therapeutic approaches for addressing skin aging and rejuvenation.

About the Authors

Michael Kahn, PhD

Michael Kahn, PhD, is a professor of cancer biology and molecular medicine at the Beckman Research Institute, City of Hope in Duarte, California.

Paul Scott Premo

Paul Scott Premo is the executive director of Genesis Molecular Technologies, Inc. in Austin, Texas.

References

1. Kahn M. Taking the road less traveled - the therapeutic potential of CBP/β-catenin antagonists. Expert Opin Ther Targets. 2021;25(9):701-719. doi:10.1080/14728222.2021.1992386

2. ΒSTEM6. Michal Morrison. 2023. Accessed November 14, 2023. https://www.michalmorrison.com/pages/science.

3. The findings have been noted by Michael Kahn, PhD, and Paul Scott Premo, in conjunction with Zoe Draelos, MD, of Dermatology Consulting Services, PLLC, in High Point, North Carolina (unpublished data, 2023).