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

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

Nature communications (2020-04-26)
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, Daohong Zhou
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
β-Glycerophosphate disodium salt hydrate, BioUltra, suitable for cell culture, suitable for plant cell culture, ≥99% (titration)
Sigma-Aldrich
Bcl-w (Minus C-Terminus) human, >95% (SDS-PAGE), recombinant, expressed in E. coli, buffered aqueous glycerol solution
Sigma-Aldrich
PZ15227, ≥98% (HPLC)
Millipore
Anti-FLAG® M2 Magnetic Beads, affinity isolated antibody
Sigma-Aldrich
Oil Red O, certified by the Biological Stain Commission
Sigma-Aldrich
Hexadimethrine bromide, ≥94% (titration)
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L-Ascorbic acid, powder, suitable for cell culture, γ-irradiated
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Propidium iodide, ≥94.0% (HPLC)
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Apyrase from potato, recombinant, expressed in Pichia pastoris, ATPase ≥1000 units/mg protein, lyophilized powder