title: A Chemical Probe for the ATAD2 Bromodomain.
abstract: ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. Paul.A.Bamborough@gsk.com.
authors.forename: Paul
authors.identifier: 0000-0001-9479-2894
authors.initials: P
authors.lastname: Bamborough
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Chun-Wa
authors.identifier: 0000-0002-2480-3110
authors.initials: CW
authors.lastname: Chung
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. Emmanuel.H.Demont@gsk.com.
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Furze
authors.affiliation: Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: Andrew J
authors.identifier: 0000-0002-6312-4436
authors.initials: AJ
authors.lastname: Bannister
authors.affiliation: Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: Ka Hing
authors.initials: KH
authors.lastname: Che
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Hawa
authors.initials: H
authors.lastname: Diallo
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Clement
authors.initials: C
authors.lastname: Douault
authors.affiliation: Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117, Heidelberg, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.affiliation: Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: Tony
authors.identifier: 0000-0002-8918-4162
authors.initials: T
authors.lastname: Kouzarides
authors.affiliation: Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117, Heidelberg, Germany.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Michon
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Mitchell
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Rab K
authors.identifier: 0000-0002-2666-3326
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117, Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Rau
authors.affiliation: Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, UK.
authors.forename: Samuel
authors.initials: S
authors.lastname: Robson
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.|AstraZeneca, Milton Road, Cambridge, CB4 OWG, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheppard
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Upton
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Watson
keywords: bioisosteres; conformation analysis; epigenetics; fluorine; medicinal chemistry