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Chem Biol. 2014 May 22;21(5):596-607. doi: 10.1016/j.chembiol.2014.02.017. Epub 2014 Apr 3.

Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site.

Author information

1
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
3
Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
4
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
5
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: xzhang@sanfordburnham.org.
6
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: ysu@sanfordburnham.org.

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.

PMID:
24704507
PMCID:
PMC4035439
DOI:
10.1016/j.chembiol.2014.02.017
[Indexed for MEDLINE]
Free PMC Article
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