title: The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor.
abstract: Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
authors.affiliation: Candidate Discovery, ‡Discovery Biology, §DMPK, GlaxoSmithKline Les Ulis, Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 Avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Gosmini
authors.forename: Van Loc
authors.initials: VL
authors.lastname: Nguyen
authors.forename: Jérôme
authors.initials: J
authors.lastname: Toum
authors.forename: Christophe
authors.initials: C
authors.lastname: Simon
authors.forename: Jean-Marie G
authors.initials: JM
authors.lastname: Brusq
authors.forename: Gael
authors.initials: G
authors.lastname: Krysa
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.forename: Alizon M
authors.initials: AM
authors.lastname: Riou-Eymard
authors.forename: Eric V
authors.initials: EV
authors.lastname: Boursier
authors.forename: Lionel
authors.initials: L
authors.lastname: Trottet
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Hugh
authors.initials: H
authors.lastname: Clark
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Leanne
authors.initials: L
authors.lastname: Cutler
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.forename: Rejbinder
authors.initials: R
authors.lastname: Kaur
authors.forename: Antonia J
authors.initials: AJ
authors.lastname: Lewis
authors.forename: Mark B
authors.initials: MB
authors.lastname: Schilling
authors.forename: Peter E
authors.initials: PE
authors.lastname: Soden
authors.forename: Simon
authors.initials: S
authors.lastname: Taylor
authors.forename: Ann L
authors.initials: AL
authors.lastname: Walker
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Walker
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodème
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018797:Cell Cycle Proteins; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D000634:Aminoquinolines; D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D001565:Benzoates; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011804:Quinolines; D014157:Transcription Factors; C000593790:4-(1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C542964:1,2,3,4-tetrahydroquinoline