Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic Acid (CD3254)

Abstract

Three unreported analogs of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogs of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254) are described, and evaluated for their retinoid-X-receptor (RXR)-selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL); though, treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the 7 modeled novel compounds, all analogs stimulate RXR-regulated transcription in mammalian-2-hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic-acid-receptor (RAR) compared to all-trans-retinoic acid, with select analogs also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

Analysis of differential secondary effects of novel rexinoids: select rexinoid X receptor ligands demonstrate differentiated side effect profiles

“…; Jurutka et al. ), and EC 50 s comparable to bexarotene (Table ) can be synthesized that, with the correct chemistry and binding profile, may alleviate or minimize thyroid hormone axis side effects. At a concentration of 1 × 10 −7 mol/L, compounds 2 , 5 , 6 , 7 , 10 , 11 , 12 , 13 , and 14 demonstrate at least 85% (or more) of the activity of T3 alone (second bar from left), with less inhibition than 1 (bexarotene), and indeed 2 , 5 , 6 , 7 , 10 , 12 , and 13 are statistically the same as T3 alone (using a two‐tailed heteroscedastic t ‐test).…”

“…; Jurutka et al. ). The cells were cotransfected using a human RXR binding domain (BD) vector, a human RXR activation domain (AD) vector, a luciferase reporter gene containing BD‐binding sites, and Renilla control plasmid, using 2 μ L/well of Express‐IN transfection reagent (Thermo Fisher Scientific, Lafayette, CO) that was allowed to incubate for 24 h with the cells.…”

A review of the molecular design and biological activities of RXR agonists

“…This molecule presented an EC 50 value of 34 nM in HCT‐116 colon cancer cells, which is superior to the EC 50 value for 2 , 55 nM . The acrylic acid analogue CD3254 ( 20 ) was also reported as a potent and selective RXR agonist (EC 50 = 13 ± 3 nM in HCT‐116 cells) . Another set of similar molecules reported by the group of Jurutka, compounds 21 to 24 , appear to be more potent, demonstrate higher efficacy, and are likely to cause side effects than 2 .…”

“…An apoptotic assay of treated CTCL cells using sodium butyrate as a control (100% dead) indicated that, after treatment with 100 nM of the compounds, 2 and molecules 22 to 24 killed ~50% of the cells while 21 caused ~70% cell death. The results also indicated that modification of 2 with more polar atoms in the aromatic ring that bears the carboxylic acid may increase the ability to activate RAR (% RAR agonistic activity at 100 nM = 27 ± 6, 28 ± 5, 31 ± 6, and 24 ± 4 for 21 to 24 in transfected HCT‐116 cells, respectively) and the ability to activate RXR (analogue 21 ) …”

“…The acrylic acid analogue CD3254 ( 20 ) was also reported as a potent and selective RXR agonist (EC 50 = 13 ± 3 nM in HCT‐116 cells) . Another set of similar molecules reported by the group of Jurutka, compounds 21 to 24 , appear to be more potent, demonstrate higher efficacy, and are likely to cause side effects than 2 . The analogues 21 (EC 50 = 44 ± 12 nM), 22 (EC 50 = 50 ± 10 nM), 23 (EC 50 = 42 ± 3 nM), and 24 (EC 50 = 15 ± 2 nM) showed RXR activity compared with 2, EC 50 = 55 ± 6, in transfected HCT‐116 cells, demonstrating that improvements in potency and selectivity of 2 can be achieved through drug design.…”