Open AccessIdentification of a New RXRα Antagonist Targeting the Coregulator-Binding Site
Author(s) -
Fan Chen,
Jie Liu,
MingFeng Huang,
Mengjie Hu,
Ying Su,
Xiaokun Zhang
Publication year - 2014
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml5000405
Subject(s) - transactivation , retinoid x receptor , microbiology and biotechnology , virtual screening , chemistry , antagonist , small molecule , ligand (biochemistry) , binding site , receptor , biology , transcription factor , biochemistry , nuclear receptor , drug discovery , gene
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 ( K d = 4.88 × 10 -7 M) 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.