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

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.

Authors:
; ; ;  [1]
  1. MIT
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002562
Resource Type:
Journal Article
Journal Name:
Nat. Chem. Biol.
Additional Journal Information:
Journal Volume: 6; Journal Issue: 08, 2010
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AFFINITY; APOPTOSIS; CAPACITY; CRYSTALLOGRAPHY; DISEASES; FUNCTIONALS; HYDROCARBONS; MUTAGENESIS; NEOPLASMS; PRESSING; PROBES; PROTEINS; SENSITIZERS; SPECIFICITY; TARGETS

Citation Formats

Stewart, Michelle L, Fire, Emiko, Keating, Amy E, Walensky, Loren D, and DFCI). The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. United States: N. p., 2010. Web. doi:10.1038/nchembio.391.
Stewart, Michelle L, Fire, Emiko, Keating, Amy E, Walensky, Loren D, & DFCI). The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. United States. https://doi.org/10.1038/nchembio.391
Stewart, Michelle L, Fire, Emiko, Keating, Amy E, Walensky, Loren D, and DFCI). 2010. "The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer". United States. https://doi.org/10.1038/nchembio.391.
@article{osti_1002562,
title = {The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer},
author = {Stewart, Michelle L and Fire, Emiko and Keating, Amy E and Walensky, Loren D and DFCI)},
abstractNote = {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.},
doi = {10.1038/nchembio.391},
url = {https://www.osti.gov/biblio/1002562}, journal = {Nat. Chem. Biol.},
number = 08, 2010,
volume = 6,
place = {United States},
year = {Mon Aug 30 00:00:00 EDT 2010},
month = {Mon Aug 30 00:00:00 EDT 2010}
}