title: Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides.
abstract: Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.
authors.affiliation: Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Paul.a.Bamborough@gsk.com
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Hawa
authors.initials: H
authors.lastname: Diallo
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Goodacre
authors.forename: Laurie
authors.initials: L
authors.lastname: Gordon
authors.forename: Antonia
authors.initials: A
authors.lastname: Lewis
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Seal
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Woodrow
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000096:biosynthesis; D005454:Fluorescence Polarization; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000737:chemistry; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D014157:Transcription Factors / Q000737:chemistry; D000092468:Bromodomain Containing Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018797:Cell Cycle Proteins; D016207:Cytokines; D007555:Isoxazoles; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D013449:Sulfonamides; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human