The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

The development of selective inhibitors for discrete anti-apoptotic Bcl-2 Family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such 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.