title: Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site.
abstract: Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding pocket (LBP). Here, we report the identification and characterization of a new RXRα transcriptional antagonist by using structure-based virtual screening. The new antagonist binds with submicromolar affinity to RXRα (Kd= 4.88 × 10-7M) and selectively inhibits RXRα transactivation. The compound does not bind to the LBP but to a hydrophobic groove on the surface of RXRα. The new compound also effectively suppresses AKT activation and promotes apoptosis of cancer cells in a RXRα-dependent manner by inhibiting tRXRα interaction with the p85α subunit of PI3K. Thus, the compound represents a new RXRα modulator that regulates the nongenomic actions of RXRα by surface binding.
authors: School of Pharmaceutical Sciences, Xiamen University , Xiamen 361005, China ; Sanford-Burnham Medical Research Institute , 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors: Fan
authors: F
authors: Chen
authors: School of Pharmaceutical Sciences, Xiamen University , Xiamen 361005, China.
authors: Jie
authors: J
authors: Liu
authors: School of Pharmaceutical Sciences, Xiamen University , Xiamen 361005, China.
authors: Mingfeng
authors: M
authors: Huang
authors: School of Pharmaceutical Sciences, Xiamen University , Xiamen 361005, China.
authors: Mengjie
authors: M
authors: Hu
authors: School of Pharmaceutical Sciences, Xiamen University , Xiamen 361005, China ; Sanford-Burnham Medical Research Institute , 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors: Ying
authors: Y
authors: Su
authors: School of Pharmaceutical Sciences, Xiamen University , Xiamen 361005, China ; Sanford-Burnham Medical Research Institute , 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors: Xiao-Kun
authors: XK
authors: Zhang
keywords: RXRα; RXRα antagonist; coregulator-binding site; nongenomic actions; virtual screening