一种小分子Smac模拟物可增强TRAIL和TNFα介导的细胞死亡。

A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death.

作者信息

Li Lin, Thomas Ranny Mathew, Suzuki Hidetaka, De Brabander Jef K, Wang Xiaodong, Harran Patrick G

机构信息

Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.

出版信息

Science. 2004 Sep 3;305(5689):1471-4. doi: 10.1126/science.1098231.

DOI:10.1126/science.1098231

PMID:15353805

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 (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.

摘要

我们描述了一种Smac小分子模拟物的合成及其性质。Smac是一种促凋亡蛋白，其作用机制是解除凋亡抑制蛋白（IAP）介导的对半胱天冬酶活性的抑制。该化合物可与X染色体编码的IAP（XIAP）、细胞IAP 1（cIAP - 1）和细胞IAP 2（cIAP - 2）结合，并与肿瘤坏死因子α（TNFα）和TNF相关凋亡诱导配体（TRAIL）协同作用，在人癌细胞中有效诱导半胱天冬酶激活和凋亡。该分子使得对IAP蛋白在TRAIL和TNF受体信号传导过程中所起作用进行了及时、无偏倚的评估。该化合物还是开发IAP拮抗剂的先导结构，这些拮抗剂可能对癌症和炎症性疾病的治疗有用。