A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death-Reference-Cited by-同舟云学术

A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death

Published:2004-09-03 Issue:5689 Volume:305 Page:1471-1474
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Li Lin¹²,Thomas Ranny Mathew¹²,Suzuki Hidetaka¹²,De Brabander Jef K.¹²,Wang Xiaodong¹²,Harran Patrick G.¹²

Affiliation:

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.

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 α (TNFα) 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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