title: Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe.
abstract: p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.
authors.forename: Philip G
authors.identifier: 0000-0002-8614-7155
authors.initials: PG
authors.lastname: Humphreys
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Peter D
authors.initials: PD
authors.lastname: Craggs
authors.forename: Laurie
authors.initials: L
authors.lastname: Gordon
authors.affiliation: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hayhow
authors.forename: Jameed
authors.initials: J
authors.lastname: Hussain
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Jones
authors.forename: Matthew
authors.initials: M
authors.lastname: Lindon
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: Jessica F
authors.initials: JF
authors.lastname: Renaux
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.forename: David F
authors.initials: DF
authors.lastname: Tough
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability; D051548:Histone Acetyltransferases / Q000737:chemistry*; D006801:Humans; D008567:Membranes, Artificial; D051379:Mice; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D000072417:Protein Domains; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050880:p300-CBP Transcription Factors / Q000737:chemistry*; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D008567:Membranes, Artificial; D015335:Molecular Probes; D010880:Piperidines; D011724:Pyridazines; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000620974:GSK4027; C501179:KAT2A protein, human