Dinaciclib Interacts with the Acetyl-Lysine Recognition Site of Bromodomains

 

https://en.wikipedia.org/wiki/Dinaciclib

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.