Publication Date:
2004-09-09
Description:
We describe the synthesis and properties of a small molecule mimic of Smac, a pro-apoptotic protein that functions by relieving inhibitor-of-apoptosis protein (IAP)-mediated suppression of caspase activity. The compound binds to X chromosome- encoded IAP (XIAP), cellular IAP 1 (cIAP-1), and cellular IAP 2 (cIAP-2) and synergizes with both tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL) to potently induce caspase activation and apoptosis in human cancer cells. The molecule has allowed a temporal, unbiased evaluation of the roles that IAP proteins play during signaling from TRAIL and TNF receptors. The compound is also a lead structure for the development of IAP antagonists potentially useful as therapy for cancer and inflammatory diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Lin -- Thomas, Ranny Mathew -- Suzuki, Hidetaka -- De Brabander, Jef K -- Wang, Xiaodong -- Harran, Patrick G -- P01 CA95471/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2004 Sep 3;305(5689):1471-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15353805" target="_blank"〉PubMed〈/a〉
Keywords:
Alkynes/chemical synthesis/chemistry/metabolism/*pharmacology
;
*Apoptosis
;
Apoptosis Regulatory Proteins
;
Biotinylation
;
*Carrier Proteins/chemistry/metabolism
;
Caspase Inhibitors
;
Caspases/metabolism
;
Cell Line, Tumor
;
Computer Simulation
;
Dimerization
;
Dipeptides/chemical synthesis/chemistry/metabolism/*pharmacology
;
Diynes
;
Glioblastoma
;
Humans
;
Inhibitor of Apoptosis Proteins
;
Intracellular Signaling Peptides and Proteins
;
Membrane Glycoproteins/metabolism/*pharmacology
;
*Mitochondrial Proteins/chemistry/metabolism
;
*Molecular Mimicry
;
NF-kappa B/metabolism
;
Poly(ADP-ribose) Polymerases/metabolism
;
Protein Binding
;
Protein Conformation
;
Protein Engineering
;
Proteins/metabolism
;
Signal Transduction
;
TNF-Related Apoptosis-Inducing Ligand
;
Tetrazoles/chemical synthesis/chemistry/metabolism/*pharmacology
;
Tumor Necrosis Factor-alpha/metabolism/*pharmacology
;
X-Linked Inhibitor of Apoptosis Protein
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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