CDC-like kinase and Dual-specificity tyrosine-regulated kinase family (CLK and DYRK family kinases) (CLK and DYRK family kinases)

The CLK (CDC-like kinase) and DYRK (Dual-specificity tyrosine-regulated kinase) families are closely related groups of serine/threonine kinases within the CMGC superfamily that play pivotal roles in cellular homeostasis. CLKs (CLK1-4) are master regulators of alternative pre-mRNA splicing, acting by phosphorylating serine/arginine-rich (SR) proteins to control spliceosome assembly and site selection [5, 16, 21]. DYRKs (DYRK1A, 1B, 2, 3, 4) are dual-specificity kinases that autophosphorylate on tyrosine for activation but primarily phosphorylate substrates on serine or threonine residues to regulate the cell cycle, neuronal differentiation, and signaling pathways like Wnt and NFAT [1, 15, 19]. Dysregulation of these kinases is strongly linked to neurodegenerative disorders such as Alzheimer's disease and Down syndrome, where DYRK1A contributes to tau hyperphosphorylation and cognitive deficits [4, 7, 11]. They are also implicated in various malignancies, including glioblastoma and breast cancer, as well as inflammatory conditions like osteoarthritis [1, 12, 16]. Therapeutic strategies focus on small-molecule inhibitors such as lorecivivint and cirtuvivint, which are designed to modulate splicing or signaling to treat degenerative and oncological diseases [1, 9, 16]. However, drug development is complicated by the high structural similarity between family members, which can lead to off-target effects and potential safety concerns like genotoxicity [4, 18].

Other names

CDC-like kinasesDual-specificity tyrosine-phosphorylation-regulated kinasesLAMMER kinasesCMGC kinasesCLKsDYRKs

ATP-competitive inhibition of kinase activity to modulate alternative pre-mRNA splicing and downstream signaling pathways such as Wnt and NFAT.