Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site

Retinoid X receptor-alpha (RXR alpha) 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 RXR alpha 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 RXR alpha transcriptional antagonist by using structure-based virtual screening. The new antagonist binds with submicromolar affinity to RXR alpha (K-d = 4.88 x 10(-7) M) and selectively inhibits RXR alpha transactivation. The compound does not bind to the LBP but to a hydrophobic groove on the surface of RXR alpha. The new compound also effectively suppresses AKT activation and promotes apoptosis of cancer cells in a RXR alpha-dependent manner by inhibiting tRXR alpha interaction with the p85 alpha subunit of PI3K. Thus, the compound represents a new RXR alpha modulator that regulates the nongenomic actions of RXR alpha by surface binding.