CDC-like kinase 2 and 3 (CLK2/CLK3)

CDC-like kinase 2 (CLK2) and CDC-like kinase 3 (CLK3) are members of the dual-specificity protein kinase family that play a critical role in the regulation of gene expression through the modulation of pre-mRNA splicing [1, 4]. These kinases function by phosphorylating serine/arginine-rich (SR) proteins, which are essential components of the spliceosome machinery responsible for selecting splice sites [1, 10]. Dysregulation of CLK2 and CLK3 has been linked to various pathologies, including several types of cancer (such as breast, colorectal, and lung cancer) where they promote oncogenic splicing variants, and neurodegenerative diseases like Alzheimer's disease where they influence the splicing of the tau protein [3, 12, 14]. In drug discovery, CLK2 and CLK3 are targeted by small-molecule inhibitors that typically act as ATP-competitive antagonists, aiming to restore normal splicing patterns or selectively induce cell death in cancer cells [1, 3]. Therapeutic candidates like Lorecivivint and Cirtuvivint are currently being evaluated in clinical trials for conditions such as osteoarthritis and advanced solid tumors, highlighting the potential of these kinases as disease-modifying targets [2, 7, 11]. Structurally, they belong to the CMGC group of kinases and contain a conserved kinase domain that facilitates the transfer of phosphate groups to serine, threonine, and tyrosine residues [11, 12]. Beyond splicing, CLK2 has been implicated in the regulation of the Wnt signaling pathway and cell cycle progression, further expanding its role in tissue homeostasis and oncogenesis [7, 14]. The development of selective inhibitors remains a challenge due to the high structural homology between CLK isoforms and other related kinases like DYRK1A [9, 11].

Other names

CDC-like kinase 2CDC-like kinase 3STYhCLK2hCLK3Dual specificity protein kinase CLK2Dual specificity protein kinase CLK3

ATP-competitive inhibition of kinase activity leading to modulation of alternative splicing and reduced phosphorylation of SR proteins.