title: Modeling, synthesis and biological evaluation of potential retinoid X receptor-selective agonists: novel halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).
abstract: The synthesis of halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), known commonly as bexarotene, and their evaluation for retinoid X receptor (RXR)-specific agonist performance is described. Compound 1 is FDA approved to treat cutaneous T-cell lymphoma (CTCL); however, bexarotene treatment can induce hypothyroidism and elevated triglyceride levels, presumably by disrupting RXR heterodimer pathways for other nuclear receptors. The novel halogenated analogues in this study were modeled and assessed for their ability to bind to RXR and stimulate RXR homodimerization in an RXRE-mediated transcriptional assay as well as an RXR mammalian-2-hybrid assay. In an array of eight novel compounds, four analogues were discovered to promote RXR-mediated transcription with EC(50) values similar to that of 1 and are selective RXR agonists. Our approach also uncovered a periodic trend of increased binding and homodimerization of RXR when substituting a halogen atom for a proton ortho to the carboxylic acid on 1.
authors.affiliation: School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts&Sciences, Arizona State University, 4701 W. Thunderbird Rd., Glendale, AZ 85306, USA.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Furmick
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.forename: Angela N
authors.initials: AN
authors.lastname: Walsh
authors.forename: Joanna
authors.initials: J
authors.lastname: Yang
authors.forename: Jaskaran S
authors.initials: JS
authors.lastname: Bhogal
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Gray
authors.forename: Juan C
authors.initials: JC
authors.lastname: Baso
authors.forename: Drew O
authors.initials: DO
authors.lastname: Browder
authors.forename: Jessica L S
authors.initials: JL
authors.lastname: Prentice
authors.forename: Luis A
authors.initials: LA
authors.lastname: Montano
authors.forename: Chanh C
authors.initials: CC
authors.lastname: Huynh
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Marcus
authors.forename: Dorian G
authors.initials: DG
authors.lastname: Tsosie
authors.forename: Jungeun S
authors.initials: JS
authors.lastname: Kwon
authors.forename: Alexis
authors.initials: A
authors.lastname: Quezada
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Reyes
authors.forename: Brittney
authors.initials: B
authors.lastname: Lemming
authors.forename: Puneet
authors.initials: P
authors.lastname: Saini
authors.forename: Arjan
authors.initials: A
authors.lastname: van der Vaart
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Groy
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Marshall
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
authors.forename: Carl E
authors.initials: CE
authors.lastname: Wagner
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077610:Bexarotene; D045744:Cell Line, Tumor; D054879:Halogenation; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000378:metabolism; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D047488:Retinoid X Receptors / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene