Navitoclax (ABT-263)

Navitoclax (ABT-263) is an orally available 'BH3 mimetic'. It inhibits three anti-death proteins: BCL-2, BCL-xL, and BCL-W. It does this by slotting into their BH3 groove, which displaces the pro-death effectors BAX and BAK. That triggers the intrinsic apoptosis (cell-death) pathway. Senescent cells, the worn-out cells that build up in your tissues, lean on these same BCL-2 family proteins to survive (their anti-apoptotic program, SCAP). Navitoclax exploits that, acting as a senolytic. Chang et al. (Nature Medicine, 2016) showed oral ABT-263 cleared senescent blood stem cells in irradiated and naturally aged mice, and restored their self-renewal. That was the first in vivo proof of drug-driven senolysis with a tissue benefit. The main obstacle is a drop in platelets (thrombocytopenia), because platelets depend almost entirely on BCL-xL to survive. Gandhi et al. (JCO, 2011, Phase I) found this dose-limiting, at 325 mg/day continuous or 350 mg intermittent. Rudin et al. (Clin Cancer Res, 2012, Phase II) recorded Grade III-IV thrombocytopenia in 41% of patients. Newer BCL-xL-directed 'PROTACs', like DT2216 and PZ15227, exploit low E3-ligase levels in platelets, for similar senolytic action with less toxicity (Skwarska and Konopleva, Cancer Research, 2023). As of mid-2026, navitoclax has not entered trials for clearing senescence in healthy people.

Last reviewed: June 22, 2026

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