| The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. | |
| | |
MedLine Citation:
|
PMID: 20562877 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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:
|
Michelle L Stewart; Emiko Fire; Amy E Keating; Loren D Walensky |
Related Documents
:
|
17942397 - Shp2e76k mutant confers cytokine-independent survival of tf-1 myeloid cells by up-regul... 10463617 - Expression level of bcl-2 determines anti- or proapoptotic function. 7541577 - Implication of cyclosporine in up-regulation of bcl-2 expression and maintenance of cd8... 10340887 - Gemcitabine-induced programmed cell death (apoptosis) of human pancreatic carcinoma is ... 11179507 - Regulation of apoptosis by angiotensin ii in the heart and lungs (review). 17868907 - Ngf promotes microglial migration through the activation of its high affinity receptor:... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-06-20 |
Journal Detail:
|
Title: Nature chemical biology Volume: 6 ISSN: 1552-4469 ISO Abbreviation: Nat. Chem. Biol. Publication Date: 2010 Aug |
Date Detail:
|
Created Date: 2010-07-20 Completed Date: 2010-08-03 Revised Date: 2011-07-25 |
Medline Journal Info:
|
Nlm Unique ID: 101231976 Medline TA: Nat Chem Biol Country: United States |
Other Details:
|
Languages: eng Pagination: 595-601 Citation Subset: IM |
Affiliation:
|
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Amino Acid Sequence Apoptosis / drug effects* Caspase 3 / metabolism Caspase 7 / metabolism Cell Survival Cross-Linking Reagents Crystallography, X-Ray Cytochromes c / metabolism Enzyme Activation / drug effects Humans Immunoprecipitation Jurkat Cells Mitochondria / enzymology, metabolism Models, Molecular Molecular Sequence Data Peptides / chemical synthesis, pharmacology Protein Binding Protein Structure, Secondary Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*, chemistry*, metabolism, pharmacology bcl-2 Homologous Antagonist-Killer Protein / metabolism, physiology |
| Grant Support | |
ID/Acronym/Agency:
|
1F31CA144566/CA/NCI NIH HHS; 5P01CA92625/CA/NCI NIH HHS; 5R01GM084181/GM/NIGMS NIH HHS; P01 CA092625-08/CA/NCI NIH HHS; P01 CA092625-09/CA/NCI NIH HHS; P01 CA092625-09S1/CA/NCI NIH HHS; R01 GM084181-03/GM/NIGMS NIH HHS; R01 GM084181-04/GM/NIGMS NIH HHS; RR-15301/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Cross-Linking Reagents; 0/Peptides; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/myeloid cell leukemia sequence 1 protein; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7 |
| Comments/Corrections | |
Comment In:
|
Nat Chem Biol. 2010 Aug;6(8):566-7
[PMID:
20644540
]
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: An ATP-independent strategy for amide bond formation in antibiotic biosynthesis.
Next Document: Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disea...