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)

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in 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...

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Autores principales:	Peter W. Jurutka, Orsola di Martino, Sabeeha Reshi, Sanchita Mallick, Zhela L. Sabir, Lech J. P. Staniszewski, Ankedo Warda, Emma L. Maiorella, Ani Minasian, Jesse Davidson, Samir J. Ibrahim, San Raban, Dena Haddad, Madleen Khamisi, Stephanie L. Suban, Bradley J. Dawson, Riley Candia, Joseph W. Ziller, Ming-Yue Lee, Chang Liu, Wei Liu, Pamela A. Marshall, John S. Welch, Carl E. Wagner
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	retinoid-X-receptor retinoid rexinoid leukemia small molecule therapeutic structure–activity relationship Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0e2a47cceb6e4307aef298907165189b
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spelling	oai:doaj.org-article:0e2a47cceb6e4307aef298907165189b2021-11-25T17:55:48ZModeling, 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)10.3390/ijms2222123711422-00671661-6596https://doaj.org/article/0e2a47cceb6e4307aef298907165189b2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12371https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in 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 (<b>1</b>), 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 EC<sub>50</sub> and IC<sub>50</sub> 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 <b>1</b>.Peter W. JurutkaOrsola di MartinoSabeeha ReshiSanchita MallickZhela L. SabirLech J. P. StaniszewskiAnkedo WardaEmma L. MaiorellaAni MinasianJesse DavidsonSamir J. IbrahimSan RabanDena HaddadMadleen KhamisiStephanie L. SubanBradley J. DawsonRiley CandiaJoseph W. ZillerMing-Yue LeeChang LiuWei LiuPamela A. MarshallJohn S. WelchCarl E. WagnerMDPI AGarticleretinoid-X-receptorretinoidrexinoidleukemiasmall molecule therapeuticstructure–activity relationshipBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12371, p 12371 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	retinoid-X-receptor retinoid rexinoid leukemia small molecule therapeutic structure–activity relationship Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	retinoid-X-receptor retinoid rexinoid leukemia small molecule therapeutic structure–activity relationship Biology (General) QH301-705.5 Chemistry QD1-999 Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Zhela L. Sabir Lech J. P. Staniszewski Ankedo Warda Emma L. Maiorella Ani Minasian Jesse Davidson Samir J. Ibrahim San Raban Dena Haddad Madleen Khamisi Stephanie L. Suban Bradley J. Dawson Riley Candia Joseph W. Ziller Ming-Yue Lee Chang Liu Wei Liu Pamela A. Marshall John S. Welch Carl E. Wagner 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)
description	Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid—or NEt-4IB—in 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 (<b>1</b>), 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 EC<sub>50</sub> and IC<sub>50</sub> 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 <b>1</b>.
format	article
author	Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Zhela L. Sabir Lech J. P. Staniszewski Ankedo Warda Emma L. Maiorella Ani Minasian Jesse Davidson Samir J. Ibrahim San Raban Dena Haddad Madleen Khamisi Stephanie L. Suban Bradley J. Dawson Riley Candia Joseph W. Ziller Ming-Yue Lee Chang Liu Wei Liu Pamela A. Marshall John S. Welch Carl E. Wagner
author_facet	Peter W. Jurutka Orsola di Martino Sabeeha Reshi Sanchita Mallick Zhela L. Sabir Lech J. P. Staniszewski Ankedo Warda Emma L. Maiorella Ani Minasian Jesse Davidson Samir J. Ibrahim San Raban Dena Haddad Madleen Khamisi Stephanie L. Suban Bradley J. Dawson Riley Candia Joseph W. Ziller Ming-Yue Lee Chang Liu Wei Liu Pamela A. Marshall John S. Welch Carl E. Wagner
author_sort	Peter W. Jurutka
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)
title_short	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)
title_full	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)
title_fullStr	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)
title_full_unstemmed	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)
title_sort	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)
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0e2a47cceb6e4307aef298907165189b
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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)

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