Proteolysis targeting chimeras as senolytics: An emerging senotherapy for combating aging.

Area of Science:

• Gerontology and Molecular Biology
• Drug Discovery and Development

Background:

• Cellular senescence contributes to aging and tissue dysfunction.
• Current senolytics, often repurposed anticancer drugs, exhibit toxicities limiting their use in the elderly.
• Senescent cell clearance improves healthspan and tissue repair.

Purpose of the Study:

• To review the development of Proteolysis Targeting Chimeras (PROTACs) as senolytics (SenoTACs).
• To highlight the advantages of SenoTACs over traditional senolytics for treating aging-related diseases.
• To address the unmet need for safer and more effective anti-aging therapies.

Main Methods:

• Review of recent literature on senescence-targeting PROTACs.
• Comparison of SenoTACs with small molecule senolytics.
• Analysis of safety and efficacy profiles of emerging SenoTACs.

Main Results:

• SenoTACs selectively eliminate senescent cells via targeted protein degradation.
• SenoTACs demonstrate improved safety and efficacy compared to small molecule senolytics.
• Examples of developed SenoTACs include ARV825, PZ15227, 753B, Gal-ARV-771, and Gal-MS99.

Conclusions:

• SenoTACs represent a promising therapeutic strategy for aging-related diseases.
• The substoichiometric degradation mechanism of SenoTACs offers enhanced efficacy and reduced resistance.
• SenoTACs have the potential to overcome the toxicity limitations of current senolytics.