Structural perspective on the design of selective DYRK1B inhibitors

DYRK1B has been recently recognized as a critical therapeutic target in oncology, metabolic syndrome, and non-alcoholic fatty liver disease. However, the development of selective inhibitors for DYRK1B, has been constrained by the lack of structural information. In this study, we employed recombinant protein production, activity assays, and crystallization to elucidate the structure of DYRK1B. We present a crystal structure of DYRK1B in complex with a known inhibitor, AZ191. For comparative analysis, we provide the crystal structure of the closely related DYRK1A kinase in complex with AZ191. Our analysis identifies a distinct binding site in the hinge region of DYRK1B, which is pivotal for the design of selective inhibitors. Quantum mechanical calculations reveal a notable difference in the accessibility of the catalytic lysine between DYRK1B and DYRK1A, suggesting a potential avenue for selective inhibitor design. These findings mark a significant advancement in the quest for specific DYRK1B inhibitors, potentially offering focused efficacy compared to the current dual-specificity inhibitors targeting both DYRK1B and DYRK1A. ### Competing Interest Statement The authors have declared no competing interest.