Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)

Michael C. Heck; Carl Wagner; Pritika H. Shahani; Mairi Macneill; Aleksandra Grozic; Tamana Darwaiz; Micah Shimabuku; David G. Deans; Nathan M. Robinson; Samer H. Salama; Joseph W. Ziller; Ning Ma; Arjan Van Der Vaart; Pamela Marshall; Peter Jurutka

doi:10.1021/acs.jmedchem.6b00812

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)

Michael C. Heck
, Carl Wagner
, Pritika H. Shahani
, Mairi Macneill
, Aleksandra Grozic
, Tamana Darwaiz
, Micah Shimabuku
, David G. Deans
, Nathan M. Robinson
, Samer H. Salama
, Joseph W. Ziller
, Ning Ma
, Arjan Van Der Vaart
, Pamela Marshall
, Peter Jurutka

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

17 Scopus citations

Abstract

Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC₅₀ profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.

Original language	English (US)
Pages (from-to)	8924-8940
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	19
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00812
State	Published - Oct 13 2016

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.6b00812

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Dive into the research topics of 'Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)'. Together they form a unique fingerprint.

CCDC 1480108: Experimental Crystal Structure Determination
Heck, M. C. (Creator), Wagner, C. E. (Creator), Shahani, P. H. (Creator), Macneill, M. (Contributor), Grozic, A. (Creator), Darwaiz, T. (Creator), Shimabuku, M. (Creator), Deans, D. G. (Creator), Robinson, N. M. (Creator), Salama, S. H. (Creator), Ziller, J. W. (Creator), Ma, N. (Creator), Van Der Vaart, A. (Creator), Marshall, P. A. (Creator) & Jurutka, P. W. (Creator), The Cambridge Structural Database, 2016
DOI: 10.5517/ccdc.csd.cc1lp5fw, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1lp5fw&sid=DataCite
Dataset
CCDC 1480110: Experimental Crystal Structure Determination
Heck, M. C. (Creator), Wagner, C. E. (Creator), Shahani, P. H. (Creator), Macneill, M. (Contributor), Grozic, A. (Creator), Darwaiz, T. (Creator), Shimabuku, M. (Creator), Deans, D. G. (Creator), Robinson, N. M. (Creator), Salama, S. H. (Creator), Ziller, J. W. (Creator), Ma, N. (Creator), Van Der Vaart, A. (Creator), Marshall, P. A. (Creator) & Jurutka, P. W. (Creator), The Cambridge Structural Database, 2016
DOI: 10.5517/ccdc.csd.cc1lp5hy, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1lp5hy&sid=DataCite
Dataset
CCDC 1480111: Experimental Crystal Structure Determination
Heck, M. C. (Creator), Wagner, C. E. (Creator), Shahani, P. H. (Creator), Macneill, M. (Contributor), Grozic, A. (Creator), Darwaiz, T. (Creator), Shimabuku, M. (Creator), Deans, D. G. (Creator), Robinson, N. M. (Creator), Salama, S. H. (Creator), Ziller, J. W. (Creator), Ma, N. (Creator), Van Der Vaart, A. (Creator), Marshall, P. A. (Creator) & Jurutka, P. W. (Creator), The Cambridge Structural Database, 2016
DOI: 10.5517/ccdc.csd.cc1lp5jz, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc1lp5jz&sid=DataCite
Dataset

Cite this

Heck, M. C., Wagner, C., Shahani, P. H., Macneill, M., Grozic, A., Darwaiz, T., Shimabuku, M., Deans, D. G., Robinson, N. M., Salama, S. H., Ziller, J. W., Ma, N., Van Der Vaart, A., Marshall, P., & Jurutka, P. (2016). Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN). Journal of Medicinal Chemistry, 59(19), 8924-8940. https://doi.org/10.1021/acs.jmedchem.6b00812

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN). / Heck, Michael C.; Wagner, Carl; Shahani, Pritika H. et al.
In: Journal of Medicinal Chemistry, Vol. 59, No. 19, 13.10.2016, p. 8924-8940.

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

Heck, MC, Wagner, C, Shahani, PH, Macneill, M, Grozic, A, Darwaiz, T, Shimabuku, M, Deans, DG, Robinson, NM, Salama, SH, Ziller, JW, Ma, N, Van Der Vaart, A, Marshall, P & Jurutka, P 2016, 'Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)', Journal of Medicinal Chemistry, vol. 59, no. 19, pp. 8924-8940. https://doi.org/10.1021/acs.jmedchem.6b00812

Heck MC, Wagner C, Shahani PH, Macneill M, Grozic A, Darwaiz T et al. Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN). Journal of Medicinal Chemistry. 2016 Oct 13;59(19):8924-8940. doi: 10.1021/acs.jmedchem.6b00812

Heck, Michael C. ; Wagner, Carl ; Shahani, Pritika H. et al. / Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists : Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN). In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 19. pp. 8924-8940.

@article{c5259391c9e54f398f5e05b66ddff332,

title = "Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)",

abstract = "Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC50 profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.",

author = "Heck, \{Michael C.\} and Carl Wagner and Shahani, \{Pritika H.\} and Mairi Macneill and Aleksandra Grozic and Tamana Darwaiz and Micah Shimabuku and Deans, \{David G.\} and Robinson, \{Nathan M.\} and Salama, \{Samer H.\} and Ziller, \{Joseph W.\} and Ning Ma and \{Van Der Vaart\}, Arjan and Pamela Marshall and Peter Jurutka",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

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language = "English (US)",

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AU - Heck, Michael C.

AU - Wagner, Carl

AU - Shahani, Pritika H.

AU - Macneill, Mairi

AU - Grozic, Aleksandra

AU - Darwaiz, Tamana

AU - Shimabuku, Micah

AU - Deans, David G.

AU - Robinson, Nathan M.

AU - Salama, Samer H.

AU - Ziller, Joseph W.

AU - Ma, Ning

AU - Van Der Vaart, Arjan

AU - Marshall, Pamela

AU - Jurutka, Peter

PY - 2016/10/13

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N2 - Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC50 profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.

AB - Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC50 profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.

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JO - Journal of Medicinal Chemistry

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Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)

Abstract

ASJC Scopus subject areas

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Datasets

CCDC 1480108: Experimental Crystal Structure Determination

CCDC 1480110: Experimental Crystal Structure Determination

CCDC 1480111: Experimental Crystal Structure Determination

Cite this