title: [1,2,4]triazolo[4,3-a]phthalazines: inhibitors of diverse bromodomains.
abstract: Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.
authors: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors: Oleg
authors: O
authors: Fedorov
authors: Hannah
authors: H
authors: Lingard
authors: Chris
authors: C
authors: Wells
authors: Octovia P
authors: OP
authors: Monteiro
authors: Sarah
authors: S
authors: Picaud
authors: Tracy
authors: T
authors: Keates
authors: Clarence
authors: C
authors: Yapp
authors: Martin
authors: M
authors: Philpott
authors: Sarah J
authors: SJ
authors: Martin
authors: Ildiko
authors: I
authors: Felletar
authors: Brian D
authors: BD
authors: Marsden
authors: Panagis
authors: P
authors: Filippakopoulos
authors: Susanne
authors: S
authors: Müller
authors: Stefan
authors: S
authors: Knapp
authors: Paul E
authors: PE
authors: Brennan
mesh_terms: D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D018360:Crystallography, X-Ray; D006801:Humans; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010793:Phthalazines; D011506:Proteins; D014157:Transcription Factors; D014230:Triazoles; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C587454:BRD9 protein, human; C576521:Cecr2 protein, human; C494363:CREBBP protein, human