The MCL-1 BH3 Helix is an Exclusive MCL-1 inhibitor and

The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of Stabilized Alpha-Helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK, and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature’s solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition. Beginning with the discovery of BCL-2 at the t14;18 chromosomal breakpoint of follicular lymphoma1, the anti-apoptotic members of the BCL-2 family have emerged as key pathogenic proteins in human diseases characterized by unchecked cellular survival, such as cancer and autoimmunity2. A series of anti-apoptotic proteins including BCL-2, BCL-XL, BCL-w, MCL-1, and BFL1/A1 promote cellular survival by trapping the critical apoptosis-inducing BCL-2 homology domain 3 (BH3) α-helix of pro-apoptotic BCL-2 family members3. Cancer cells exploit this physiologic survival mechanism through anti-apoptotic Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use