Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anti-cancer effects of certain non-steroidal anti-inflammatory drugs (NSAIDs), including Sulindac. We report the synthesis and characterization of two new Sulindac analogs, K-8008 and K-8012, which exert improved anti-cancer activities over Sulindac in a RXRα- dependent manner. The new analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as new tRXRα modulators and define a new binding mechanism for regulating the nongenomic action of tRXRα.