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 AlmeidaGuangrong Zheng, Daohong Zhou

Producción científica: Articlerevisión exhaustiva

153 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Número de artículo1996
PublicaciónNature communications
Volumen11
N.º1
DOI
EstadoPublished - dic 1 2020
Publicado de forma externa

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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