Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains

ACS Chem Biol. 2013 Nov 15;8(11):2360-5. doi: 10.1021/cb4003283. Epub 2013 Sep 10.

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.

MeSH terms

  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Crystallography, X-Ray
  • Histone Chaperones
  • Humans
  • Hydrogen Bonding
  • Lysine / chemistry*
  • Models, Molecular*
  • Nuclear Proteins / chemistry
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Pyridinium Compounds / chemistry
  • Pyridinium Compounds / pharmacology*

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Histone Chaperones
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Pyridinium Compounds
  • dinaciclib
  • BRD1 protein, human
  • Lysine

Associated data

  • PDB/4KCX
  • PDB/4KD1