Cdc2-like kinase (CLK) (CLK)

Cdc2-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 splicing [1.3.1, 1.4.1]. They function by phosphorylating the arginine/serine-rich (RS) domains of SR proteins, which are essential components of the spliceosome that govern exon selection and splice site recognition [1.1.1, 1.3.4]. Beyond their primary role in splicing, CLKs are involved in critical cellular processes such as cell cycle progression, cytokinesis via Aurora B activation, and the modulation of signaling pathways like Wnt and PI3K/mTOR [1.1.1, 1.3.1, 1.3.3]. Dysregulation of CLK activity is strongly linked to various pathologies, including multiple types of cancer (e.g., triple-negative breast cancer), neurodegenerative disorders like Alzheimer's disease, and viral infections such as HIV and influenza [1.2.1, 1.3.1, 1.4.1]. In oncology, CLK-mediated aberrant splicing produces protein isoforms that promote tumor survival, metastasis, and resistance to therapy [1.1.2, 1.3.4]. Consequently, CLKs have emerged as attractive therapeutic targets, with several small-molecule inhibitors like Lorecivivint and Cirtuvivint in clinical development [1.3.1, 1.4.2]. These inhibitors typically act as ATP-competitive agents that reduce SR protein phosphorylation, thereby reprogramming the cellular splicing landscape to suppress disease-associated pathways [1.2.1, 1.3.4].

Other names

Cdc2-like kinaseCLK1CLK2CLK3CLK4STYDual-specificity protein kinase CLK

ATP-competitive inhibition of kinase activity, which prevents the phosphorylation of serine/arginine-rich (SR) proteins, thereby modulating alternative splicing of pre-mRNA and altering the expression of disease-associated protein isoforms.