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Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic
Yonghan He1, Xuan Zhang2, Jianhui Chang3
1Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
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.
Insights
Senolytics, molecules targeting senescent cells, can treat age-related diseases. A new PROTAC technology reduces platelet toxicity of Bcl-xl inhibitors, offering safer senolytic therapies.
Area of Science:
- Biochemistry
- Gerontology
- Molecular Biology
Background:
- Senolytics selectively eliminate senescent cells (SCs), showing promise for age-related diseases and healthspan extension.
- Bcl-xl inhibitors, a class of senolytics, exhibit significant platelet toxicity, limiting their therapeutic application.
- Navitoclax (ABT263) is a dual Bcl-2 and Bcl-xl inhibitor with dose-limiting thrombocytopenia.
Purpose of the Study:
- To develop a safer senolytic agent by reducing the platelet toxicity of Bcl-xl inhibitors.
- To investigate the efficacy of a novel proteolysis-targeting chimera (PROTAC) approach for senolytic therapy.
- To assess the potential of Bcl-xl PROTACs as improved senolytic agents compared to traditional inhibitors.
Main Methods:
- Conversion of navitoclax (ABT263) into a Bcl-xl PROTAC, PZ15227 (PZ), by linking it to the cereblon (CRBN) E3 ligase.
- Evaluation of PZ's toxicity on platelets and its potency against senescent cells.
- Assessment of PZ's efficacy in clearing senescent cells and rejuvenating stem/progenitor cells in naturally aged mice.
Main Results:
- PZ demonstrated reduced platelet toxicity compared to ABT263 due to lower CRBN expression in platelets.
- PZ exhibited equal or slightly enhanced potency against senescent cells compared to ABT263.
- PZ effectively cleared senescent cells and rejuvenated tissue stem and progenitor cells in aged mice without causing severe thrombocytopenia.
Conclusions:
- Bcl-xl PROTACs, exemplified by PZ, offer a promising strategy to overcome the platelet toxicity associated with Bcl-xl inhibitors.
- PROTAC technology can yield senolytic agents with improved safety and efficacy profiles.
- Further development of Bcl-xl PROTACs holds potential for safer and more potent senolytic therapies for age-related conditions.
