title: Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors.
abstract: Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Furze
authors.affiliation: §Molecular Discovery Research, Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.affiliation: §Molecular Discovery Research, Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Michon
authors.forename: Chris
authors.initials: C
authors.lastname: Wellaway
authors.forename: Nathalie
authors.initials: N
authors.lastname: Barrett
authors.forename: Angela M
authors.initials: AM
authors.lastname: Bridges
authors.forename: Peter D
authors.initials: PD
authors.lastname: Craggs
authors.forename: Hawa
authors.initials: H
authors.lastname: Diallo
authors.forename: David P
authors.initials: DP
authors.lastname: Dixon
authors.forename: Clement
authors.initials: C
authors.lastname: Douault
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Emmons
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Jones
authors.forename: Bhumika V
authors.initials: BV
authors.lastname: Karamshi
authors.forename: Kelly
authors.initials: K
authors.lastname: Locke
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Mitchell
authors.forename: Bernadette H
authors.initials: BH
authors.lastname: Mouzon
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: ∥Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, United Kingdom.
authors.forename: Andy D
authors.initials: AD
authors.lastname: Roberts
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheppard
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Watson
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D000251:Adenosine Triphosphatases