An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene. Int J Mol Sci 2022 Dec 19;23(24)
Date
12/24/2022Pubmed ID
36555852Pubmed Central ID
PMC9782500DOI
10.3390/ijms232416213Scopus ID
2-s2.0-85144580245 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.
Author List
Jurutka PW, di Martino O, Reshi S, Mallick S, Sausedo MA, Moen GA, Lee IJ, Ivan DJ, Krall TD, Peoples SJ, Perez A, Tromba L, Le A, Khadka I, Petros R, Savage BM, Salama E, Salama J, Ziller JW, Noh Y, Lee MY, Liu W, Welch JS, Marshall PA, Wagner CEAuthor
Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
HumansLeukemia
Liver X Receptors
Lymphoma, T-Cell, Cutaneous
Retinoid X Receptors
Retinoids
Skin Neoplasms
Tetrahydronaphthalenes
Triglycerides
