Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2

被引：49

作者：

Cossu, Federica ^{[1
]}

Mastrangelo, Eloise ^{[1
,2
]}

Milani, Mario ^{[1
,2
]}

Sorrentino, Graziella ^{[1
]}

Lecis, Damele ^{[3
]}

Delia, Domenico ^{[3
]}

Manzoni, Leonardo ^{[4
,5
]}

Seneci, Pierfausto ^{[5
,6
]}

Scolastico, Carlo ^{[5
,6
]}

Bolognesi, Martino ^{[1
,2
]}

机构：

[1] Univ Milan, Dept Biomol Sci & Biotechnol, I-20133 Milan, Italy

[2] CNR, INFM, I-20133 Milan, Italy

[3] Ist Nazl Tumori, Fdn IRCCS, Dept Expt Oncol, I-20133 Milan, Italy

[4] CNR, ISTM, I-20133 Milan, Italy

[5] Univ Milan, CISI, I-20133 Milan, Italy

[6] Univ Milan, Dept Organ & Ind Chem, I-20133 Milan, Italy

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2009年 / 378卷 / 02期

关键词：

Inhibition of apoptosis; SMAC/DIABLO; Peptidomimetics; XIAP; cIAP; Oncology; ALPHA-DEPENDENT APOPTOSIS; STRUCTURAL BASIS; CANCER-CELLS; PROTEIN; INHIBITION; THERAPY; BINDING; POTENT; IAPS; REFINEMENT;

D O I：

10.1016/j.bbrc.2008.10.139

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. Several compounds targeting IAPs and inducing cell death in cancer cells have been developed. Some of these are synthesized mimicking the N-terminal tetrapeptide sequence of Smac/DIABLO, the natural endogenous IAPs inhibitor. Starting from such conceptual design, we generated a library of 4-substituted azabicyclo[5.3.0]alkane Smac-mimetics. Here we report the crystal structure of the BIR3 domain from XIAP in complex with Smac037, a compound designed according to Structural principles emerging from Our previously analyzed XIAP BIR3/Smac-mimetic, complexes. In parallel, we present an in silico docking analysis of three Smac-mimetics to the BIR3 domain of cIAP1, providing general considerations for the development of high affinity lead compounds targeting three members of the IAP family. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：162 / 167

页数：6

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