{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T02:15:09Z","timestamp":1767838509574,"version":"3.49.0"},"reference-count":86,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T00:00:00Z","timestamp":1637020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1 R15 CA139364-01A2"],"award-info":[{"award-number":["1 R15 CA139364-01A2"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R15CA249617-01"],"award-info":[{"award-number":["1R15CA249617-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL128447"],"award-info":[{"award-number":["R01 HL128447"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid\u2014or NEt-4IB\u2014in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.<\/jats:p>","DOI":"10.3390\/ijms222212371","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T11:32:03Z","timestamp":1637062323000},"page":"12371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB)"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-9161","authenticated-orcid":false,"given":"Peter W.","family":"Jurutka","sequence":"first","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"},{"name":"Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7620-0290","authenticated-orcid":false,"given":"Orsola","family":"di Martino","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabeeha","family":"Reshi","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanchita","family":"Mallick","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhela L.","family":"Sabir","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lech J. P.","family":"Staniszewski","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankedo","family":"Warda","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"},{"name":"Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma L.","family":"Maiorella","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ani","family":"Minasian","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse","family":"Davidson","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samir J.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"San","family":"Raban","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dena","family":"Haddad","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madleen","family":"Khamisi","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie L.","family":"Suban","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley J.","family":"Dawson","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riley","family":"Candia","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph W.","family":"Ziller","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7082-1216","authenticated-orcid":false,"given":"Ming-Yue","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, Tempe, AZ 85201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, Tempe, AZ 85201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, Arizona State University, Tempe, AZ 85201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3530-4368","authenticated-orcid":false,"given":"Pamela A.","family":"Marshall","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6656-3672","authenticated-orcid":false,"given":"John S.","family":"Welch","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl E.","family":"Wagner","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,16]]},"reference":[{"key":"ref_1","unstructured":"Mangelsdorf, D.J.U., and Evans, R.M.K. 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