CDC-like kinase and Dual-specificity tyrosine-phosphorylation-regulated kinase (CLK/DYRK)

The CDC-like kinases (CLK1-4) and Dual-specificity tyrosine-phosphorylation-regulated kinases (DYRK1A, 1B, and 2) are closely related members of the CMGC kinase family that function as key regulators of pre-mRNA splicing and cellular signaling. CLKs primarily modulate the activity of the spliceosome by phosphorylating serine/arginine-rich (SR) proteins, thereby influencing alternative splicing patterns of numerous genes involved in cell survival and proliferation (Fededa et al., 2005, Nature). DYRK family members exhibit dual-specificity activity, autophosphorylating on tyrosine residues for activation while phosphorylating substrates on serine/threonine residues to regulate the cell cycle, microtubule dynamics, and neuronal development (Aranda et al., 2011, FASEB J). In oncology, overexpressed CLKs and DYRKs drive the production of pro-tumorigenic splice variants and promote resistance to apoptosis, making them attractive targets for small-molecule inhibitors like SM08502 (Tamura et al., 2020, Cancer Medicine). Furthermore, DYRK1A is a critical therapeutic target in neurodegenerative diseases such as Alzheimer's and Down syndrome due to its role in phosphorylating Tau protein and amyloid precursor protein (Wegiel et al., 2011, FEBS J). Clinical-stage compounds like Lorecivivint target this kinase group to modulate Wnt signaling and inflammatory pathways in conditions such as osteoarthritis (Yazici et al., 2020, Osteoarthritis and Cartilage).

Other names

CLK1CLK2CLK3CLK4DYRK1ADYRK1BDYRK2Cdc2-like kinasesDual-specificity tyrosine-regulated kinasesCMGC kinases

Small molecule inhibition of the ATP-binding site of CLK and DYRK kinases, preventing the phosphorylation of downstream substrates such as SR proteins and Tau to modulate alternative splicing and signaling pathways.