Dual-specificity tyrosine-phosphorylation-regulated kinase 1A, 1B, 2, 3, and 4 (DYRK1A/1B/2/3/4)

The Dual-specificity tyrosine-phosphorylation-regulated kinase (DYRK) family consists of five members (DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4) that serve as critical regulators of cell signaling, growth, and development [1.1.3, 1.3.1]. These kinases are characterized by their unique ability to autophosphorylate on a tyrosine residue within the activation loop for catalytic activation, while subsequently phosphorylating exogenous substrates on serine and threonine residues [1.1.1, 1.3.3]. DYRK1A is the most extensively studied member; its gene is located in the Down syndrome critical region of chromosome 21, and its overexpression is a primary driver of cognitive deficits and early-onset Alzheimer's pathology through the hyperphosphorylation of Tau protein [1.1.3, 1.4.1]. DYRK1B, also known as MIRK, is frequently overexpressed in solid tumors where it promotes the survival of quiescent cancer cells and confers resistance to chemotherapy [1.1.2, 1.3.4]. Beyond neurodegeneration and oncology, DYRK kinases are emerging as therapeutic targets for metabolic disorders. Inhibition of DYRK1A has been shown to promote the proliferation of human pancreatic beta-cells, offering a potential regenerative strategy for treating Type 1 and Type 2 diabetes [1.2.1, 1.3.2]. Other family members, such as DYRK2 and DYRK3, play specialized roles in proteasome regulation and erythropoiesis, respectively [1.3.3, 1.3.4]. Current drug development efforts focus on achieving high selectivity for specific DYRK isoforms to avoid off-target effects on related CMGC kinases like CLKs, with several candidates such as Leucettinib-21 and FRTX-02 currently undergoing clinical evaluation [1.2.2, 1.2.4].

Other names

Dual-specificity tyrosine-phosphorylation-regulated kinase familyDYRK familyMinibrain (MNB)Minibrain-related kinase (MIRK)Regulatory erythroid kinase (REDK)MNBHHP86MRD7AOMS3

ATP-competitive inhibition of the kinase catalytic domain, preventing the phosphorylation of downstream substrates such as Tau, NFAT, GLI1, and cyclin D1.