Nature communications · 2020
Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
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История · было → стало
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He Yonghan, Zhang Xuan, Chang Jianhui, Kim Ha-Neui, Zhang Peiyi, Wang Yingying, Khan Sajid, Liu Xingui, Zhang Xin, Lv Dongwen, Song Lin, Li Wen, Thummuri Dinesh, Yuan Yaxia, Wiegand Janet S, Ortiz Yuma T, Budamagunta Vivekananda, Elisseeff Jennifer H, Campisi Judith, Almeida Maria, Zheng Guangrong, Zhou Daohong
Аннотация
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.