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J. Biol. Chem., Vol. 281, Issue 24, 16643-16648, June 16, 2006

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A Structure-based Approach to Retinoid X Receptor- Inhibition^*

John L. Stebbins¹, Dawoon Jung¹, Marilisa Leone¹, Xiao-kun Zhang, and Maurizio Pellecchia²

From the Cancer Center and Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, California 92037

In this paper we describe a structure-based approach designed to identify novel ligands for retinoid X receptor- (RXR). By using a virtual approach based on a modified scoring function, we have selected 200 potential candidates on the basis of their predicted ability of docking into the ligand-binding site of the target. Subsequent experimental verification of the compounds in in vitro and cell-based assays led to the identification of a number of novel high affinity ligands for RXR. The compounds are capable of displacing 9-cis-retinoic acid with IC₅₀ values in the 10 nM and 5 µM range and exhibit marked antagonistic activity in cellular assays. The inhibitory scaffolds discovered with this method form the basis for the development of novel RXR ligands with potential therapeutic properties.

Received for publication, January 12, 2006 , and in revised form, March 21, 2006.

^* This work was supported in part by National Institutes of Health Grants CA113318 and CA109345 and DoD Grant W81 XWH-04-1-0161. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Cancer Center and Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3159; Fax: 858-713-9925; E-mail: mpellecchia{at}burnham.org.

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