Sulindac-derived RXR? modulators inhibit cancer cell growth by binding to a novel site.

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

SUBMITTER: Chen L 

PROVIDER: S-EPMC4035439 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature