Nonpeptidic and Potent Small-molecule Inhibitors of CIAP-1/2 and XIAP Proteins

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2010 Aug 6

PMID 20684551

Citations 19

Authors

Haiying Sun

Jianfeng Lu

Liu Liu

Han Yi

Su Qiu

Chao-Yie Yang

Jeffrey R Deschamps

Shaomeng Wang

Affiliations

Soon will be listed here.

Abstract

A series of compounds were designed and synthesized as antagonists of cIAP-1/2 and XIAP based upon our previously identified lead compound SM-122 (1). The most potent of these (7) binds to XIAP, cIAP-1, and cIAP-2 proteins with K(i) values of 36, <1, and <1.9 nM, respectively. Consistent with its potent binding affinities to IAPs, 7 effectively antagonizes XIAP in a cell-free caspase-9 functional assay, efficiently induces cIAP-1 degradation in cells at concentrations as low as 10 nM, and triggers activation of caspases and PARP cleavage in the MDA-MB-231 breast cancer cell line. Compound 7 potently inhibits cell growth in the MDA-MB-231 cancer cell line with an IC(50) value of 200 nM and is 9 times more potent than compound 1.

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