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) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254).
abstract: Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.
authors.affiliation: 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.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.forename: Joanna
authors.initials: J
authors.lastname: Yang
authors.forename: Jaskaran S
authors.initials: JS
authors.lastname: Bhogal
authors.forename: Johnathon C
authors.initials: JC
authors.lastname: Swierski
authors.forename: Christa R
authors.initials: CR
authors.lastname: Tabacaru
authors.forename: Luis A
authors.initials: LA
authors.lastname: Montano
authors.forename: Chanh C
authors.initials: CC
authors.lastname: Huynh
authors.forename: Rabia A
authors.initials: RA
authors.lastname: Jama
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Mahelona
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Sarnowski
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Marcus
authors.forename: Alexis
authors.initials: A
authors.lastname: Quezada
authors.forename: Brittney
authors.initials: B
authors.lastname: Lemming
authors.forename: Maria A
authors.initials: MA
authors.lastname: Tedesco
authors.forename: Audra J
authors.initials: AJ
authors.lastname: Fischer
authors.forename: Said A
authors.initials: SA
authors.lastname: Mohamed
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Ziller
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Gray
authors.forename: Arjan
authors.initials: A
authors.lastname: van der Vaart
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Marshall
authors.forename: Carl E
authors.initials: CE
authors.lastname: Wagner
mesh_terms: D003373:Coumaric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047488:Retinoid X Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C525130:CD 3254; D003373:Coumaric Acids; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes