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Selective Elimination of Senescent Cancer Cells by Galacto-Modified PROTACs.
Chang, Mengyang; Gao, Feng; Gnawali, Giri; Xu, Hang; Dong, Yue; Meng, Xiang; Li, Wenpan; Wang, Zhiren; Lopez, Byrdie; Carew, Jennifer S; Nawrocki, Steffan T; Lu, Jianqin; Zhang, Qing-Yu; Wang, Wei.
Afiliación
  • Chang M; Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
  • Gao F; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
  • Gnawali G; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
  • Xu H; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
  • Dong Y; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
  • Meng X; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
  • Li W; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
  • Wang Z; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
  • Lopez B; Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
  • Carew JS; Department of Medicine, University of Arizona, Tucson, Arizona 85721, United States.
  • Nawrocki ST; University of Arizona Cancer Center, University of Arizona, Tucson, Arizona 85721, United States.
  • Lu J; Department of Medicine, University of Arizona, Tucson, Arizona 85721, United States.
  • Zhang QY; University of Arizona Cancer Center, University of Arizona, Tucson, Arizona 85721, United States.
  • Wang W; Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
J Med Chem ; 67(9): 7301-7311, 2024 May 09.
Article en En | MEDLINE | ID: mdl-38635879
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 ß-galactosidase (SA-ß-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-ß-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos / Senescencia Celular / Proteolisis / Galactosa Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Profármacos / Senescencia Celular / Proteolisis / Galactosa Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos