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- Title
The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.
- Authors
Stewart, Michelle L.; Fire, Emiko; Keating, Amy E.; Walensky, Loren D.
- Abstract
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.
- Subjects
APOPTOSIS prevention; MOLECULAR probes; CANCER cells; CANCER treatment; R factors; X-ray crystallography; X-ray mutagenesis
- Publication
Nature Chemical Biology, 2010, Vol 6, Issue 8, p595
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.391