Development of novel Bexarotene analogs for treating cutaneous T-cell lymphomas

Abstract

Bexarotene, a drug approved 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. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, fourteen novel analogs were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXRE-mediated luciferase reporter assays. In addition, these analogs were tested for their effectiveness to inhibit proliferation in CTCL cells relative to bexarotene. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds possess similar or 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 development of more highly efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes. NCUIRE Undergraduate Research Program (ASU) & National Institutes of Health (NIH) CA140285 (to PWJ, CEW and PAM) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.