Sulindac-Derived RXRα Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site

Retinoid X receptor-alpha (RXR alpha), 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 RXR alpha-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXR alpha (tRXR alpha) with the p85 alpha subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXR alpha ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXR alpha LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXR alpha modulators and define a binding mechanism for regulating the nongenomic action of tRXR alpha.