# 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.

## Sources

- Chang J, Wang Y, Shao L, et al.. (2016). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Medicine. https://doi.org/10.1038/nm.4010
- Gandhi L, Camidge DR, de Oliveira MR, et al.. (2011). Phase I Study of Navitoclax (ABT-263), a Novel Bcl-2 Family Inhibitor, in Patients With Small-Cell Lung Cancer and Other Solid Tumors. Journal of Clinical Oncology. https://doi.org/10.1200/JCO.2010.31.6208
- Rudin CM, Hann CL, Garon EB, et al.. (2012). Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-11-3090
- Skwarska A, Konopleva M. (2023). BCL-xL Targeting to Induce Apoptosis and to Eliminate Chemotherapy-Induced Senescent Tumor Cells: From Navitoclax to Platelet-Sparing BCL-xL PROTACs. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-23-2804

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_Canonical: https://longevity-switzerland.com/en/glossary/navitoclax · Part of Longevity Cities · Updated 2026-06-22_