Development of Novel Bexarotene Analogs for Treating Cutaneous T‐Cell Lymphomas

Agonists are chemical compounds that bind to and activate their cognate receptors allowing for the propagation of a downstream signal. Receptor agonists exhibit varying pharmacodynamic properties, including binding affinity and receptor specificity. Bexarotene, a drug approved by the FDA in 1999 for the treatment of cutaneous T‐cell lymphoma (CTCL), is classified as a rexinoid due to its ability to act as a retinoid X receptor (RXR) agonist with high specificity. RXR is known to associate with other receptors in the nuclear receptor superfamily as either permissive or nonpermissive heterodimers that then modulate gene expression of numerous target genes. In a similar fashion, RXR‐selective rexinoids, such as bexarotene, also act as RXR agonists and influence RXR homodimerization leading to the induction of apoptosis and inhibition of cell proliferation in human cancers. In fact, several studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, the side effects of bexarotene therapy are significant and can include cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor, thyroid hormone receptor, and liver X receptor signaling, respectively. Thus, the discovery of compounds with greater RXR specificity is an important goal in cancer therapeutics and drug development. In the current study, we have evaluated 14 novel analogs for their potential to bind RXR through modeling and via an RXR‐RXR mammalian‐2‐hybrid system. In addition, RXR response element‐mediated luciferase reporter assays were employed to determine the degree of transcriptional activation induced by each analog. Moreover, using a cell proliferation assay, these analogs were tested for their effectiveness to inhibit proliferation in CTCL cells relative to bexarotene. Finally, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Current results suggest that these new compounds possess similar or even enhanced therapeutic potential, as several of our novel rexinoids display more selective RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR‐ligand relationships and permits the development of more highly efficacious pharmaceutical drugs. Our results reveal that modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent bexarotene compound, potentially leading to improved patient outcomes.