Structural and Biochemical Studies of DYRK1A Kinase

Abstract

DYRK1A is a protein kinase and target for drug design. It was first discovered in neurological tissues and linked to neurological disease, particularly Down Syndrome and Alzheimer’s disease, where few treatment options are available. This has led to numerous studies seeking inhibitors of DYRK1A as new drugs for disease treatment, since inappropriate DYRK1A expression and activity contributes not only to Down Syndrome and Alzheimer’s disease, but also to other diseases including Parkinson disease, Pick’s disease, cancer and HPV (human papilloma virus).Development of new treatment strategies for these diseases is badly needed and development of specific inhibitors of DYRK1A provides a promising new avenue. Presented herein are studies designed to uncover mechanism in DYRK1A inhibition and provide insight for improved drug design. Crystallographic studies of DYRK1A in both inhibited and unliganded forms are presented. Structures with tight binding inhibitors DYR533, DYR542, DYR636 were determined and revealed their unique binding motifs, which include a new hydrogen bonding network. Regions of the inhibitors that do not contribute to binding were also identified, leading to suggestions for additional inhibitor improvements. Structures without ligand and with an ATP analog were also determined, which provide additional insight into drug efficacy. Inhibition studies under cellular conditions were also undertaken, revealing additional mechanistic insight.