RESUMO
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.
Assuntos
Senescência Celular , Galactose , Pró-Fármacos , Proteólise , Humanos , Animais , Senescência Celular/efeitos dos fármacos , Galactose/química , Galactose/farmacologia , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Camundongos , Proteólise/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Galactosidase/metabolismo , Camundongos Nus , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células A549 , Etoposídeo/farmacologia , Senoterapia/farmacologia , Senoterapia/química , Quimera de Direcionamento de ProteóliseRESUMO
Site-selective modification of biologically relevant secondary amines in peptides, proteins, and natural products has been challenging due to the similar reactivity between primary and secondary amines. Even for the secondary amines, their reactivities are significantly influenced by their structures and environment. Herein, we report a ynone Michael bioconjugation method for selective modification of secondary amines in unprotected peptides and proteins and complex natural products. We show that fine tuning the electronic effect of the ynones enables controlling the Michael acceptor reactivity for the selective reaction with the structurally different secondary amines in densely functionalized complex structures and complicated biological environment.
