Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure.
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.
Jaye
Michael C
MC
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
Krawiec
John A
JA
Campobasso
Nino
N
Smallwood
Angela
A
Qiu
Chunyan
C
Lu
Quinn
Q
Kerrigan
John J
JJ
De Los Frailes Alvaro
Maite
M
Laffitte
Bryan
B
Liu
Wu-Schyong
WS
Marino
Joseph P
JP
Meyer
Craig R
CR
Nichols
Jason A
JA
Parks
Derek J
DJ
Perez
Paloma
P
Sarov-Blat
Lea
L
Seepersaud
Sheila D
SD
Steplewski
Klaudia M
KM
Thompson
Scott K
SK
Wang
Ping
P
Watson
Mike A
MA
Webb
Christine L
CL
Haigh
David
D
Caravella
Justin A
JA
Macphee
Colin H
CH
Willson
Timothy M
TM
Collins
Jon L
JL
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
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