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).
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 EC50profiles 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.
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Michael C
MC
Heck
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Carl E
CE
Wagner
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Pritika H
PH
Shahani
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Mairi
M
MacNeill
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Aleksandra
A
Grozic
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Tamana
T
Darwaiz
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Micah
M
Shimabuku
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
David G
DG
Deans
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Nathan M
NM
Robinson
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Samer H
SH
Salama
Department of Chemistry, University of California, Irvine , 576 Rowland Hall, Irvine, California 92697, United States.
Joseph W
JW
Ziller
Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States.
Ning
N
Ma
Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States.
Arjan
A
van der Vaart
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Pamela A
PA
Marshall
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University , 4701 West Thunderbird Road, Glendale, Arizona 85306, United States.
Peter W
PW
Jurutka
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D000077610:Bexarotene; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009525:Niacin / Q000031:analogs & derivatives / Q000494:pharmacology; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D047488:Retinoid X Receptors; D051779:Sterol Regulatory Element Binding Proteins; D013764:Tetrahydronaphthalenes; D009525:Niacin; D000077610:Bexarotene; D056284:Histone Deacetylase 1