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

Cruickshank-Taylor, Alexis B., Kozora, Jacob S., Carew, Jennifer S., Nawrocki, Steffan T., Wang, Wei·2025·The Journal of Pharmacology and Experimental Therapeutics
DOI 10.1016/j.jpet.2025.103752
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Abstract

Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives aging-related phenotypes. Clearance of senescent cells decreases chronic, low-grade inflammation and restores tissue repair capacity, thus improving human health and lifespan. Senolytics that selectively eliminate senescent cells have become a promising antiaging strategy. To date, current senolytics are largely developed by repurposing anticancer agents. Therefore, senolytics usually possess various on- and off-target toxicities. These toxicities could preclude their clinical use as antiaging agents, as elderly people are more susceptible to adverse drug effects than young individuals. Proteolysis targeting chimeras as senolytics, termed "SenoTACs," are attractive for more effective treatment of aging-related diseases. In comparison to small molecule inhibitors, SenoTACs can eliminate senescent cells by degrading targeted proteins in a substoichiometric manner, providing better target ability, longer-lasting therapeutic effect, broadened target capability, and decreased drug resistance. Recent efforts have led to the development of several senescence-targeting proteolysis targeting chimeras, including ARV825, PZ15227, 753B, Gal-ARV-771, and Gal-MS99, which exhibit selective senolytic activity and improved safety and efficacy profiles when compared with small molecule inhibitors. In this minireview, we summarize the development of the emer…

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Metadata

Authors
Cruickshank-Taylor, A. B., Kozora, J. S., Carew, J. S., Nawrocki, S. T., & Wang, W.
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2025-11
Volume
392
Issue
11
Pages
103752
ISSN
0022-3565
DOI
10.1016/j.jpet.2025.103752
Cited by
4
References
15
Language
en
Licence
Funders
  • The University of Arizona Health Sciences
  • University of Arizona
  • National Institutes of Health National Cancer Institute (T32 CA009213)

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