한빛사 논문
Yonghan He1,8, Xuan Zhang2,8, Jianhui Chang3,8, Ha-Neui Kim4,8, Peiyi Zhang2, Yingying Wang3, Sajid Khan1, Xingui Liu1, Xin Zhang1, Dongwen Lv1, Lin Song3, Wen Li1, Dinesh Thummuri1, Yaxia Yuan1, Janet S. Wiegand1, Yuma T. Ortiz1, Vivekananda Budamagunta1, Jennifer H. Elisseeff5, Judith Campisi6,7, Maria Almeida4, Guangrong Zheng2,9,* & Daohong Zhou1,9,*
1 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA. 2 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA. 3 Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 4 Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 5 Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA. 6 Buck Institute for Research on Aging, Novato, CA, USA. 7 Lawrence Berkeley National Laboratory, Berkeley, CA, USA. 8These authors contributed equally: Yonghan He, Xuan Zhang, Jianhui Chang, Ha-Neui Kim. 9These authors jointly supervised this work: Guangrong Zheng, Daohong Zhou.
*Corresponding author
Abstract
Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
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