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)

Carl Wagner; Peter Jurutka; Pamela Marshall; Thomas L. Groy; Arjan Van Der Vaart; Joseph W. Ziller; Julie K. Furmick; Mark E. Graeber; Erik Matro; Belinda V. Miguel; Ivy T. Tran; Jungeun Kwon; Jamie N. Tedeschi; Shahram Moosavi; Amina Danishyar; Joshua S. Philp; Reina O. Khamees; Jevon N. Jackson; Darci K. Grupe; Syed L. Badshah; Justin W. Hart

doi:10.1021/jm900496b

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)

Carl Wagner, Peter Jurutka, Pamela Marshall, Thomas L. Groy, Arjan Van Der Vaart, Joseph W. Ziller, Julie K. Furmick, Mark E. Graeber, Erik Matro, Belinda V. Miguel, Ivy T. Tran, Jungeun Kwon, Jamie N. Tedeschi, Shahram Moosavi, Amina Danishyar, Joshua S. Philp, Reina O. Khamees, Jevon N. Jackson, Darci K. Grupe, Syed L. BadshahJustin W. Hart

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K_i and EC₅₀ values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.

Original language	English (US)
Pages (from-to)	5950-5966
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	19
DOIs	https://doi.org/10.1021/jm900496b
State	Published - Oct 8 2009

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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CCDC 738930: Experimental Crystal Structure Determination
Wagner, C. (Creator), Jurutka, P. (Creator), Marshall, P. (Creator), Groy, T. L. (Creator), Van Der Vaart, A. (Creator), Ziller, J. W. (Creator), Furmick, J. K. (Creator), Graeber, M. E. (Creator), Matro, E. (Creator), Miguel, B. V. (Creator), Tran, I. T. (Creator), Kwon, J. (Creator), Tedeschi, J. N. (Creator), Moosavi, S. (Creator), Danishyar, A. (Creator), Philp, J. S. (Creator), Khamees, R. O. (Creator), Jackson, J. N. (Creator), Grupe, D. K. (Creator), Badshah, S. L. (Creator), Hart, J. W. (Creator) & Wagner, C. E. (Creator), The Cambridge Structural Database, 2010
DOI: 10.5517/ccssxgx, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccssxgx&sid=DataCite
Dataset
CCDC 738925: Experimental Crystal Structure Determination
Wagner, C. (Creator), Jurutka, P. (Creator), Marshall, P. (Creator), Groy, T. L. (Creator), Van Der Vaart, A. (Creator), Ziller, J. W. (Creator), Furmick, J. K. (Creator), Graeber, M. E. (Creator), Matro, E. (Creator), Miguel, B. V. (Creator), Tran, I. T. (Creator), Kwon, J. (Creator), Tedeschi, J. N. (Creator), Moosavi, S. (Creator), Danishyar, A. (Creator), Philp, J. S. (Creator), Khamees, R. O. (Creator), Jackson, J. N. (Creator), Grupe, D. K. (Creator), Badshah, S. L. (Creator), Hart, J. W. (Creator) & Wagner, C. E. (Creator), The Cambridge Structural Database, 2010
DOI: 10.5517/ccssx9r, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccssx9r&sid=DataCite
Dataset
CCDC 738927: Experimental Crystal Structure Determination
Wagner, C. (Creator), Jurutka, P. (Creator), Marshall, P. (Creator), Groy, T. L. (Creator), Van Der Vaart, A. (Creator), Ziller, J. W. (Creator), Furmick, J. K. (Creator), Graeber, M. E. (Creator), Matro, E. (Creator), Miguel, B. V. (Creator), Tran, I. T. (Creator), Kwon, J. (Creator), Tedeschi, J. N. (Creator), Moosavi, S. (Creator), Danishyar, A. (Creator), Philp, J. S. (Creator), Khamees, R. O. (Creator), Jackson, J. N. (Creator), Grupe, D. K. (Creator), Badshah, S. L. (Creator), Hart, J. W. (Creator) & Wagner, C. E. (Creator), The Cambridge Structural Database, 2010
DOI: 10.5517/ccssxct, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccssxct&sid=DataCite
Dataset

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Wagner, C., Jurutka, P., Marshall, P., Groy, T. L., Van Der Vaart, A., Ziller, J. W., Furmick, J. K., Graeber, M. E., Matro, E., Miguel, B. V., Tran, I. T., Kwon, J., Tedeschi, J. N., Moosavi, S., Danishyar, A., Philp, J. S., Khamees, R. O., Jackson, J. N., Grupe, D. K., ... Hart, J. W. (2009). 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). Journal of Medicinal Chemistry, 52(19), 5950-5966. https://doi.org/10.1021/jm900496b

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). / Wagner, Carl ; Jurutka, Peter ; Marshall, Pamela et al.
In: Journal of Medicinal Chemistry, Vol. 52, No. 19, 08.10.2009, p. 5950-5966.

Research output: Contribution to journal › Article › peer-review

Wagner, C , Jurutka, P , Marshall, P, Groy, TL, Van Der Vaart, A, Ziller, JW, Furmick, JK, Graeber, ME, Matro, E, Miguel, BV, Tran, IT, Kwon, J, Tedeschi, JN, Moosavi, S, Danishyar, A, Philp, JS, Khamees, RO, Jackson, JN, Grupe, DK, Badshah, SL & Hart, JW 2009, '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)', Journal of Medicinal Chemistry, vol. 52, no. 19, pp. 5950-5966. https://doi.org/10.1021/jm900496b

Wagner C , Jurutka P , Marshall P, Groy TL, Van Der Vaart A, Ziller JW et al. 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). Journal of Medicinal Chemistry. 2009 Oct 8;52(19):5950-5966. doi: 10.1021/jm900496b

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title = "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)",

abstract = "This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.",

author = "Carl Wagner and Peter Jurutka and Pamela Marshall and Groy, {Thomas L.} and {Van Der Vaart}, Arjan and Ziller, {Joseph W.} and Furmick, {Julie K.} and Graeber, {Mark E.} and Erik Matro and Miguel, {Belinda V.} and Tran, {Ivy T.} and Jungeun Kwon and Tedeschi, {Jamie N.} and Shahram Moosavi and Amina Danishyar and Philp, {Joshua S.} and Khamees, {Reina O.} and Jackson, {Jevon N.} and Grupe, {Darci K.} and Badshah, {Syed L.} and Hart, {Justin W.}",

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AU - Wagner, Carl

AU - Jurutka, Peter

AU - Marshall, Pamela

AU - Groy, Thomas L.

AU - Van Der Vaart, Arjan

AU - Ziller, Joseph W.

AU - Furmick, Julie K.

AU - Graeber, Mark E.

AU - Matro, Erik

AU - Miguel, Belinda V.

AU - Tran, Ivy T.

AU - Kwon, Jungeun

AU - Tedeschi, Jamie N.

AU - Moosavi, Shahram

AU - Danishyar, Amina

AU - Philp, Joshua S.

AU - Khamees, Reina O.

AU - Jackson, Jevon N.

AU - Grupe, Darci K.

AU - Badshah, Syed L.

AU - Hart, Justin W.

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N2 - This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.

AB - This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated forRXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable Ki and EC50 values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.

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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)

Abstract

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Datasets

CCDC 738930: Experimental Crystal Structure Determination

CCDC 738925: Experimental Crystal Structure Determination

CCDC 738927: Experimental Crystal Structure Determination

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