navitoclax

Navitoclax, also known as ABT-263, is an oral small-molecule inhibitor of anti-apoptotic BCL-2 family proteins, including BCL-2, BCL-XL, and BCL-W. It was developed as a cancer therapy intended to promote apoptosis in tumor cells that depend on these proteins for survival.

Mechanism of action is as a BH3 mimetic. Navitoclax binds the hydrophobic groove of BCL-2 family members, displacing pro-apoptotic proteins. This shifts balance toward apoptosis, triggering mitochondrial outer membrane permeabilization, cytochrome c release, and activation of caspases in susceptible cancer cells.

In clinical development, navitoclax has been evaluated in phase I and II trials for a range of malignancies, including small cell lung cancer, non-small cell lung cancer, leukemias, and lymphomas, often in combination with chemotherapy or targeted therapies. A major challenge observed in trials is dose-limiting thrombocytopenia, attributed to inhibition of BCL-XL which is essential for platelet survival. This toxicity limited broad use and influenced the development trajectory. The field has increasingly favored more selective BCL-2 inhibitors, such as venetoclax (ABT-199), to reduce platelet-related side effects. Nevertheless, navitoclax has continued to be studied in some ongoing or niche combinatorial trials.

Regulatory status: navitoclax is not approved by major authorities for any cancer indication and is considered investigational in many jurisdictions. Its development has largely given way to selective BCL-2 inhibitors, although research remains ongoing in certain trial settings.