Synthesis and SAR study of modulators inhibiting tRXRα-dependent AKT activation

RXRα represents an intriguing and unique target for pharmacologic interventions. We recently showed that Sulindac and a designed analog could bind to RXRα and modulate its biological activity, including inhibition of the interaction of an N-terminally truncated RXRα (tRXRα) with the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K). Here we report the synthesis, testing and SAR of a series of novel analogs of Sulindac as potential modulators for inhibiting tRXRα-dependent AKT activation. A new compound 30 was identified to have improved biological activity.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 28 New Sulindac analogs as modulators of tRXRα-dependent AKT activation were synthesized. ► Binding assay was used to test the 28 compounds for SAR study. ► A new scaffold was found with improved biological properties.