title: The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist.
abstract: Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiological processes including hepatic gluconeogenesis, lipid metabolism, circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both RORalpha and RORgamma. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of RORalpha and RORgamma but not RORbeta. T0901317 was found to directly bind to RORalpha and RORgamma with high affinity (K(i) = 132 and 51 nM, respectively), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed RORalpha/gamma-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by RORalpha at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compound's LXR activity. In summary, T0901317 represents a novel chemical probe to examine RORalpha/gamma function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small molecules can be used to target the RORs for therapeutic intervention in metabolic and immune disorders.
authors.affiliation: The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.forename: Juliana J
authors.initials: JJ
authors.lastname: Conkright
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Monica A
authors.initials: MA
authors.lastname: Istrate
authors.forename: Scott A
authors.initials: SA
authors.lastname: Busby
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Garcia-Ordonez
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000819:agonists* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D006845:Hydrocarbons, Fluorinated; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018168:Receptors, Retinoic Acid; D013449:Sulfonamides; D000097768:Retinoic Acid Receptor gamma; C539738:RORA protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides