title: Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.
abstract: The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 Avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.forename: Romain
authors.initials: R
authors.lastname: Gosmini
authors.forename: Jérôme
authors.initials: J
authors.lastname: Toum
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Clément
authors.forename: Mélanie
authors.initials: M
authors.lastname: Barnathan
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Brusq
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Mordaunt
authors.forename: Richard M
authors.initials: RM
authors.lastname: Grimes
authors.forename: Miriam
authors.initials: M
authors.lastname: Crowe
authors.forename: Olivier
authors.initials: O
authors.lastname: Pineau
authors.forename: Myriam
authors.initials: M
authors.lastname: Ajakane
authors.forename: Alain
authors.initials: A
authors.lastname: Daugan
authors.forename: Phillip
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Leanne
authors.initials: L
authors.lastname: Cutler
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Haynes
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Smithers
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Uings
authors.forename: Antonia
authors.initials: A
authors.lastname: Lewis
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Nigel
authors.initials: N
authors.lastname: Parr
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodème
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000096:biosynthesis; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D004285:Dogs; D044127:Epigenesis, Genetic; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010539:Permeability; D017434:Protein Structure, Tertiary; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D016632:Apolipoprotein A-I; D001569:Benzodiazepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C505693:APOA1 protein, human; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C554645:molibresib