Sulindac-derived RXRα Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2014 Apr 8

PMID 24704507

Citations 17

Authors

Liqun Chen

Zhi-Gang Wang

Alexander E Aleshin

Fan Chen

Jiebo Chen

Fuquan Jiang

Gulimiran Alitongbieke

Zhiping Zeng

Yue Ma

Mingfeng Huang

Hu Zhou

Gregory Cadwell

Jian-Feng Zheng

Pei-Qiang Huang

Robert C Liddington

Xiao-Kun Zhang

Ying Su

Affiliations

Soon will be listed here.

Abstract

Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRα-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRα modulators and define a binding mechanism for regulating the nongenomic action of tRXRα.

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