Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence

Ziqiang Fan; Yingdong Tong; Ziyue Yang; Shuai Wang; Tiantian Huang; Deying Yang; Qingyong Ni; Mingwang Zhang; Diyan Li; Mingyao Yang; Xiaolan Fan

doi:10.1016/j.exger.2024.112359

Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence

Exp Gerontol. 2024 Feb:186:112359. doi: 10.1016/j.exger.2024.112359. Epub 2024 Jan 7.

Authors

Affiliations

¹ Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China.
² Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China.
³ Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, 610106 Chengdu, China.
⁴ Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China. Electronic address: yangmingyao@sicau.edu.cn.
⁵ Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan 611130, PR China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China. Electronic address: xiaolanfan@sicau.edu.cn.

PMID: 38184267
DOI: 10.1016/j.exger.2024.112359

Abstract

Aging is a gradual process of natural change that occurs after reaching sexual maturity. It is also a known risk factor for many chronic diseases. Recent research has shown that senolytics can extend the lifespans and health spans of model organisms, and they have also been demonstrated effective in treating age-related diseases. In this study, we conducted a high-throughput screening of 156 drugs that targeted the PI3K/AKT/mTOR pathway to identify potential senolytic medications. Among these drugs, PF-04691502 was selected for further investigation to understand its molecular mechanism of action. Our findings indicate that PF-04691502, a dual inhibitor of PI3K/AKT and mTOR, specifically eliminates senescent cells. It reduces the expression levels of key markers of cellular senescence, such as SA-β-Gal, senescence-associated secretory phenotypes (SASPs) and p16^INK4a. Additionally, PF-04691502 inhibits the phosphorylation of S6K and AKT, leading to the apoptosis of senescent cells. These results suggest that PF-04691502 holds promise as a new senolytic drug. This paper provides important insights into the potential application of PF-04691502 in the study of cell senescence.

Keywords: AKT; PF-04691502; Senescent cells; Senolytic; mTOR.

MeSH terms

Cellular Senescence
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt* / metabolism
Pyridones*
Pyrimidines*
Senotherapeutics*
TOR Serine-Threonine Kinases / metabolism

Substances

2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
Senotherapeutics
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
TOR Serine-Threonine Kinases
Pyridones
Pyrimidines