Selective Elimination of Senescent Cancer Cells by Galacto-Modified PROTACs

Mengyang Chang, Feng Gao, Giri Gnawali, Hang Xu, Yue Dong, Xiang Meng, Wenpan Li, Zhiren Wang, Byrdie Lopez, Jennifer S. Carew, Steffan T. Nawrocki, Jianqin Lu, Qing Yu Zhang, Wei Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Although the selective and effective clearance of senescent cancer cells can improve cancer treatment, their development is confronted by many challenges. As part of efforts designed to overcome these problems, prodrugs, whose design is based on senescence-associated β-galactosidase (SA-β-gal), have been developed to selectively eliminate senescent cells. However, chemotherapies relying on targeted molecular inhibitors as senolytic drugs can induce drug resistance. In the current investigation, we devised a new strategy for selective degradation of target proteins in senescent cancer cells that utilizes a prodrug composed of the SA-β-gal substrate galactose (galacto) and the proteolysis-targeting chimeras (PROTACs) as senolytic agents. Prodrugs Gal-ARV-771 and Gal-MS99 were found to display senolytic indexes higher than those of ARV-771 and MS99. Significantly, results of in vivo studies utilizing a human lung A549 xenograft mouse model demonstrated that concomitant treatment with etoposide and Gal-ARV-771 leads to a significant inhibition of tumor growth without eliciting significant toxicity.

Original languageEnglish (US)
Pages (from-to)7301-7311
Number of pages11
JournalJournal of Medicinal Chemistry
Volume67
Issue number9
DOIs
StatePublished - May 9 2024

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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