title: Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.
abstract: Bromodomain-containing proteins are considered atypical kinases, but their potential to interact with kinase inhibitors is unknown. Dinaciclib is a potent inhibitor of cyclin-dependent kinases (CDKs), which recently advanced to Phase III clinical trials for the treatment of leukemia. We determined the crystal structure of dinaciclib in complex with CDK2 at 1.7 Å resolution, revealing an elaborate network of binding interactions in the ATP site, which explains the extraordinary potency and selectivity of this inhibitor. Remarkably, dinaciclib also interacted with the acetyl-lysine recognition site of the bromodomain testis-specific protein BRDT, a member of the BET family of bromodomains. The binding mode of dinaciclib to BRDT at 2.0 Å resolution suggests that general kinase inhibitors ("hinge binders") possess a previously unrecognized potential to act as protein-protein inhibitors of bromodomains. The findings may provide a new structural framework for the design of next-generation bromodomain inhibitors using the vast chemical space of kinase inhibitors.
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, Florida 33612, United States.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Martin
authors.forename: Sanne H
authors.initials: SH
authors.lastname: Olesen
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
authors.forename: Ernst
authors.initials: E
authors.lastname: Schönbrunn
mesh_terms: D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D006860:Hydrogen Bonding; D007212:Indolizines; D008239:Lysine / Q000737:chemistry*; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D007212:Indolizines; D008239:Lysine; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; C553669:dinaciclib; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins