Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity

Yonghan He, Xuan Zhang, Jianhui Chang, Ha-Neui Kim, Peiyi Zhang, Yingying Wang, Sajid Khan, Xingui Liu, Xin Zhang, Dongwen Lv, Lin Song, Wen Li, Dinesh Thummuri, Yaxia Yuan, Janet S. Wiegand, Yuma T. Ortiz, Vivekananda Budamagunta, Jennifer H. Elisseeff, Judith Campisi, Maria Almeida, Guangrong Zheng () and Daohong Zhou ()
Additional contact information
Yonghan He: University of Florida
Xuan Zhang: University of Florida
Jianhui Chang: University of Arkansas for Medical Sciences
Ha-Neui Kim: University of Arkansas for Medical Sciences
Peiyi Zhang: University of Florida
Yingying Wang: University of Arkansas for Medical Sciences
Sajid Khan: University of Florida
Xingui Liu: University of Florida
Xin Zhang: University of Florida
Dongwen Lv: University of Florida
Lin Song: University of Arkansas for Medical Sciences
Wen Li: University of Florida
Dinesh Thummuri: University of Florida
Yaxia Yuan: University of Florida
Janet S. Wiegand: University of Florida
Yuma T. Ortiz: University of Florida
Vivekananda Budamagunta: University of Florida
Jennifer H. Elisseeff: Johns Hopkins School of Medicine
Judith Campisi: Buck Institute for Research on Aging
Maria Almeida: University of Arkansas for Medical Sciences
Guangrong Zheng: University of Florida
Daohong Zhou: University of Florida

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15838-0

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