Navitoclax (ABT-263)

Navitoclax (ABT-263) is an orally bioavailable BH3 mimetic that inhibits BCL-2, BCL-xL, and BCL-W by binding their BH3-interaction groove and displacing pro-apoptotic effectors BAX and BAK, triggering the intrinsic apoptosis pathway. Senescent cells upregulate BCL-2 family members through their anti-apoptotic programme (SCAP); navitoclax exploits this as a senolytic. Chang et al. (Nature Medicine, 2016) showed oral ABT-263 depleted senescent hematopoietic stem cells in irradiated and naturally aged mice and restored self-renewal, providing the first in vivo evidence of pharmacological senolysis with tissue benefit. The primary obstacle is BCL-xL-dependent thrombocytopenia: platelets depend almost exclusively on BCL-xL for survival. 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. BCL-xL-directed PROTACs such as DT2216 and PZ15227 exploit low E3-ligase expression in platelets for comparable senolytic activity with reduced toxicity (Skwarska and Konopleva, Cancer Research, 2023). As of mid-2026, navitoclax has not entered trials for senescence clearance in healthy individuals.