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Science 305 (5689): 1471-1474

Copyright © 2004 by the American Association for the Advancement of Science

A Small Molecule Smac Mimic Potentiates TRAIL- and TNF{alpha}-Mediated Cell Death

Lin Li,1* Ranny Mathew Thomas,1* Hidetaka Suzuki,1* Jef K. De Brabander,1{dagger} Xiaodong Wang,1,2{dagger} Patrick G. Harran1{dagger}

Abstract: 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} (TNF{alpha}) 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.

1 Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390–9038, USA.
2 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390–9038, USA.

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* These authors contributed equally to the work.

{dagger} To whom correspondence should be addressed. E-mail: pharra{at}biochem.swmed.edu (P.G.H.), xwang{at}biochem.swmed.edu (X.W.), jdebra{at}biochem.swmed.edu (J.K.D.)


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