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Proteolysis-Targeting Chimera Technology for Therapeutic Applications

By 22nd May 2020No Comments

The following study was conducted by Scientists from Department of Pharmacodynamics, College of Pharmacy, Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA; Department of Pharmaceutical Sciences, Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA; Buck Institute for Research on Aging, Novato, CA, USA; Lawrence Berkeley National Laboratory, Berkeley, CA, USA. Study is published in Nature Communications Journal as detailed below.

Nature Communications; Volume 11, Article Number: 1996; (2020)

Using Proteolysis-Targeting Chimera Technology to Reduce Navitoclax Platelet Toxicity and Improve its Senolytic Activity


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.


Nature Communications



He, Y., X. Zhang, et al. (2020). “Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity.” Nature Communications 11(1): 1996.