title: Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.
abstract: ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Furze
authors.affiliation: ∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.affiliation: ∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Michon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheppard
authors.forename: Heather
authors.initials: H
authors.lastname: Barnett
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: Emma J
authors.initials: EJ
authors.lastname: Jones
authors.forename: Bhumika
authors.initials: B
authors.lastname: Karamshi
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Mitchell
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: ∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Rau
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Watson
authors.affiliation: ∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Werner
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D009287:Naphthyridines; D000251:Adenosine Triphosphatases; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities