Structural perspective on the design of selective DYRK1B inhibitors

Abstract

AbstractDYRK1B kinase recently emerged as a potential target in cancer, metabolic syndrome, and nonalcoholic fatty liver disease, but the lack of structural information hinders the design of selective DYRK1B inhibitors. Here, we provide a method for recombinant production, activity assays, crystallization conditions and a high resolution crystal structure of DYRK1B in complex with nonselective AZ191 inhibitor. A structure of a closely related DYRK1A kinase with AZ191 is also solved to facilitate comparative analysis. The analysis allows to identify a convenient anchor point at the hinge region of DYRK1B which should permit future development of selective inhibitors of potential advantage over currently available dual specificity DYRK1B/1A inhibitors.