A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death.
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.
Li
Lin
L
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
Thomas
Ranny Mathew
RM
Suzuki
Hidetaka
H
De Brabander
Jef K
JK
Wang
Xiaodong
X
Harran
Patrick G
PG
D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D019921:Biotinylation; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003198:Computer Simulation; D019281:Dimerization; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053280:Diynes; D005909:Glioblastoma; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein
C491032:1,6-bis(4,7-diaza-6-methyl-5-oxo-3-((2-((5-(phenylthio)tetrazol-1-yl)methyl)pyrrolidin-1-yl)carbonyl)octyloxy)-2,4-hexadiyne; D000480:Alkynes; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C412403:DIABLO protein, human; D004151:Dipeptides; D053280:Diynes; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D011506:Proteins; C572769:RMT5265; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases