Identification Of New Sulindac Derivatives Targeting RXRα And Their Mechanism Of Action

The abnormal expression,localization or function of RXRa,one of the important members of the nuclear receptor superfamily,is associated with the development of cancer.Consistently,ligands of RXRa have shown promising therapeutic effects against cancer,making RXRa one of the most important drug targets.Sulindac derivatives K-80003 and K-8008 can bind RXRa to inhibit the interaction of truncated RXRa(tRXRa)with p85a and induce cancer cell apoptosis.The binding site of K-8008 to RXRa is different from the classical RXRa ligand.We previously identified K-8008 derivatives as potential anticancer agents targeting RXRa.In this study,we evaluated a series of K-8008 derivatives by reporter assay and MTT and found that new derivatives 8b and 18a with stronger binding to RXRa and improved apoptotic activities in cancer cell.Binding of 8b and 18a to RXRa was confirmed by fluorescence quenching assay.Western Blot showed that 8b and 18a induce RXRa-dependent apoptosis indicated by PARP cleavage better than K-8008.In studying the molecular mechanism of their action,we examined their effect on mTOR activation.EGF and amino acids significantly activated the mTOR pathway.When used together with 8b and 18a,we found that 8b failed to inhibit mTOR activation,while 18a strongly inhibited mTOR activation induced by EGF in a RXRa-dependent manner.Furthermore,18a also inhibited the activation of the amino acid-induced mTOR pathway by inhibiting the interaction of p62 with TRAF6 partly through RXRa-mediated mechanism.In conclusion,our results identified new K-8008 derivatives with improved RXRa binding and apoptotic activities and a new RXRa-mediated anti-cancer pathway.