CDC-like kinase 1-4 (CLK1-4) (CLK1-4)

CDC-like kinase 1-4 (CLK1-4) are a family of dual-specificity protein kinases that play a fundamental role in the regulation of pre-mRNA alternative splicing [1, 2, 8]. They function by phosphorylating serine/arginine-rich (SR) proteins, which are essential components of the spliceosome that dictate splice site selection [1, 3, 7]. By modulating the phosphorylation state of these factors, CLKs control the production of diverse protein isoforms from a single gene, thereby influencing various cellular processes such as cell cycle progression, apoptosis, and signal transduction [2, 4, 8]. Interestingly, CLK1 and CLK4 also act as 'biological thermometers', as their activity is highly sensitive to physiological temperature changes, allowing cells to adapt their splicing patterns to thermal stress [2, 6, 9]. Dysregulation of CLK activity is implicated in a wide range of human pathologies, including various cancers where aberrant splicing promotes tumor growth and survival [4, 5, 8]. In neurodegenerative conditions like Alzheimer's disease, CLKs contribute to the pathological hyperphosphorylation of tau and the imbalance of tau splice variants [5, 10, 13]. Furthermore, many viruses, such as influenza and HIV, hijack the host's CLK-mediated splicing machinery to facilitate their own replication [5, 7, 15]. Consequently, CLK1-4 have emerged as attractive therapeutic targets [8, 12]. Several small-molecule inhibitors, such as Lorecivivint and Cirtuvivint, are currently being evaluated in clinical trials for indications ranging from osteoarthritis to advanced solid tumors [3, 8, 12]. However, achieving high selectivity between CLK isoforms and avoiding off-target effects on related kinases like DYRKs remains a significant pharmacological challenge [1, 5, 11, 13].

Other names

STY [3, 4, 7]CLK [3, 7]LAMMER kinase [3, 4, 7, 8, 9]CDC2-like kinase [3, 4, 7, 8, 11]

Inhibition of kinase activity and subsequent modulation of alternative splicing [1, 2, 8]