BCL-xL Targeting to Induce Apoptosis and to Eliminate Chemotherapy-Induced Senescent Tumor Cells: From Navitoclax to Platelet-Sparing BCL-xL PROTACs.

Abstract

Restoring apoptotic cell death is a critical goal for cancer therapy. One of the primary mechanisms by which cancer cells evade death and maintain survival in the face of stress signals is by overexpression of prosurvival B-cell lymphoma 2 (BCL2) family members such as BCL2, BCL-xL, and MCL1, which suppress the intrinsic (mitochondrial) pathway of apoptosis through complex protein and membrane interactions. While these antiapoptotic proteins have been validated as potent therapeutic targets, synthesis of their inhibitors remained challenging for decades mainly due to the presence of a difficult to target, highly hydrophobic groove on the surface. The groove serves as a binding site for the BH3 domain of corresponding proapoptotic partners, which leads to their sequestration and prevents apoptosis. In 2008, a Cancer Research article by Tse and colleagues, led by Dr. Steven Elmore from Abbott Laboratories, reported the discovery of the first orally bioavailable BCL2/BCL-xL inhibitor, navitoclax (ABT-263), marking the onset of an era of "BH3 mimetics" in cancer therapeutics and changing the therapeutic landscape especially for leukemia. Here, we reflect on how this landmark study fueled development of small-molecule BH3 mimetics like venetoclax and seek to indicate new strategies and future directions for improving the clinical activity of navitoclax for hematologic malignancies. See related article by Tse and colleagues, Cancer Res 2008;68:3421-3428.