Senolytics ⇒ New research to reduce platelet toxicity and improve senolytic activity of senolytics

[AlbertY]

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

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.

https://www.nature.com/articles/s41467-020-15838-0

[AlbertY]

One major obstacle of anti-aging drugs is the adversary effect... Somehow people just can not stand anti-aging drugs has any side-effect. Blood toxicity is one of the side effects of senolytic drugs: platelet has a very similar survival mechanism as senescent cells (considering they are both ready to die but not dead yet), senolytic drugs can kill platelets. It will result in bleeding, even worse if it's internal.

I used to work with ABT263 (aka navitoclax). It's one of the most powerful and safe senolytics, at least in mice. Looking forward to the day people figure out how to do it clinically...

[NewLifeScience]

Thank you Albert. I have been looking for more information about Senolytics and their behaviours.