CDC-like kinase (CLK)

CDC-like kinases (CLKs) are a family of four dual-specificity protein kinases (CLK1, CLK2, CLK3, and CLK4) that serve as master regulators of pre-mRNA alternative splicing [1, 6]. They function by phosphorylating Serine/Arginine-rich (SR) proteins, which are essential components of the spliceosome that dictate splice site selection [2, 17]. By modulating the phosphorylation status of these SR proteins, CLKs influence the diversity of the cellular proteome and the relative abundance of protein isoforms [1, 16]. Dysregulation of CLK activity is strongly implicated in various human pathologies, particularly in "splicing-addicted" cancers where they promote the production of oncogenic splice variants that drive cell proliferation and survival [3, 11, 14]. Additionally, CLKs play significant roles in neurodegenerative diseases like Alzheimer's by affecting the alternative splicing of genes such as MAPT (Tau), and in viral infections where they are hijacked for viral RNA processing [10, 15]. Pharmaceutical development focuses on small-molecule inhibitors that target the ATP-binding pocket of CLKs to modulate splicing for therapeutic benefit [5, 8]. Clinical candidates like lorecivivint and cirtuvivint are currently being investigated for conditions ranging from osteoarthritis to advanced solid tumors [8, 17].

Other names

Cdc2-like kinaseSTY kinaseLAMMER kinaseDual-specificity protein kinase CLK

Inhibition of CLK kinase activity to modulate alternative splicing of pre-mRNA by reducing phosphorylation of serine/arginine-rich (SR) proteins, thereby altering spliceosome assembly and exon selection.