title: Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit.
abstract: The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.
authors.affiliation: Pfizer Worldwide Medicinal Chemistry,  Pfizer Worldwide R&D , Ramsgate Road, Sandwich CT13 9NJ, United Kingdom.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Gerwyn
authors.initials: G
authors.lastname: Bish
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bunnage
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cook
authors.forename: Oleg
authors.initials: O
authors.lastname: Federov
authors.forename: Brian S
authors.initials: BS
authors.lastname: Gerstenberger
authors.forename: Hannah
authors.initials: H
authors.lastname: Jones
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Brian
authors.initials: B
authors.lastname: Marsden
authors.forename: Karl
authors.initials: K
authors.lastname: Nocka
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Primiano
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ralph
authors.forename: Nunzio
authors.initials: N
authors.lastname: Sciammetta
authors.forename: John D
authors.initials: JD
authors.lastname: Trzupek
mesh_terms: D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015335:Molecular Probes / Q000138:chemical synthesis / Q000494:pharmacology*; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D052999:Quinazolinones / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000096926:Benzenesulfonamides; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D015335:Molecular Probes; D009687:Nuclear Proteins; D052999:Quinazolinones; D013449:Sulfonamides; D014157:Transcription Factors; C577942:2-methoxy-N-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins