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

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

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1
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute , 12902 Magnolia Drive, Tampa, Florida 33612, United States.

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.

PMID:
24007471
PMCID:
PMC3846258
DOI:
10.1021/cb4003283
[Indexed for MEDLINE]
Free PMC Article

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