title: Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure.
abstract: Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 as an LXR ligand. GSK3987 recruits the steroid receptor coactivator-1 to human LXRalpha and LXRbeta with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.
authors.affiliation: GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jaye
authors.forename: John A
authors.initials: JA
authors.lastname: Krawiec
authors.forename: Nino
authors.initials: N
authors.lastname: Campobasso
authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
authors.forename: Chunyan
authors.initials: C
authors.lastname: Qiu
authors.forename: Quinn
authors.initials: Q
authors.lastname: Lu
authors.forename: John J
authors.initials: JJ
authors.lastname: Kerrigan
authors.forename: Maite
authors.initials: M
authors.lastname: De Los Frailes Alvaro
authors.forename: Bryan
authors.initials: B
authors.lastname: Laffitte
authors.forename: Wu-Schyong
authors.initials: WS
authors.lastname: Liu
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
authors.forename: Craig R
authors.initials: CR
authors.lastname: Meyer
authors.forename: Jason A
authors.initials: JA
authors.lastname: Nichols
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Paloma
authors.initials: P
authors.lastname: Perez
authors.forename: Lea
authors.initials: L
authors.lastname: Sarov-Blat
authors.forename: Sheila D
authors.initials: SD
authors.lastname: Seepersaud
authors.forename: Klaudia M
authors.initials: KM
authors.lastname: Steplewski
authors.forename: Scott K
authors.initials: SK
authors.lastname: Thompson
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Mike A
authors.initials: MA
authors.lastname: Watson
authors.forename: Christine L
authors.initials: CL
authors.lastname: Webb
authors.forename: David
authors.initials: D
authors.lastname: Haigh
authors.forename: Justin A
authors.initials: JA
authors.lastname: Caravella
authors.forename: Colin H
authors.initials: CH
authors.lastname: Macphee
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Jon L
authors.initials: JL
authors.lastname: Collins
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008156:Luciferases / Q000235:genetics; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000814:Aniline Compounds; D004268:DNA-Binding Proteins; C504517:GSK 3987; D008024:Ligands; D000071518:Liver X Receptors; D008301:Maleimides; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D008156:Luciferases; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1