Senolytics: Venetoclax

Recently it was discovered that human senescent cells have pro-surival pathways that allow them to be resistant to apoptosis, using a hypothesis-driven bioinformatics-based approach scientists discovered that Dasatibnib and Quercetin are senolytics and can remove "death resistant" senescent cells. Using a similar approach researchers at two labs discovered the drug Navitoclax also had senolytic properties and was able to remove senesent cells from tissue and shown here and here. However Navitoclax has potentially serious side effects and can cause bleeding by affecting platelets and can cause neutropenia, while newer similar drugs may have less of these effects.

Venetoclax (ABT-199) is a drug that shares some similar characterists to Navitoclax however with reduced side effects and off target effects. We are interested in exploring the potential of this drug and there is some promise of additive effect with Dastinib if cancer research is any indication as Venetoclax appears to reduce resistance to Dasatinib thus making it easier to destroy the target cell. Venetoclax focuses on the BCL-2 pathway and is part of a family that comprises two broad categories of prosurvival (Bcl-2, Bcl-XL, Bcl-W, Mcl-1, and A1) and proapoptotic (Bax, Bak, Bim, Bid, Puma, Bad, Noxa, Bik, Bmf, and Hrk) proteins. In general, the balance between these proteins determines whether a cell lives or dies and manipulation of these proteins is of significant interest to Senolytics. 

Excitingly another senolytic was recently discovered ABT-737 which also targets the same BCL family and has shown promising results, in this study they also tested ABT-199 and conclude it has additive effects when used with drugs that target two other major BCL pathways (BCL-W and BCL-XL) which they identify as the primary pathways that control resistance to cell death in senescent cells. It would therefore make sense to combine additive drugs like Venetoclax with drugs such as Dasatinib or ABT-737 to potentially increase the efficacy of Senolytic therapy.