CLK (CDC-like kinase family)

Class

Small molecule kinase inhibitor (splicing modulator)

Pathway

Pre-mRNA splicing regulation via SR-protein phosphorylation

CLK (CDC-like kinase) proteins are a small family of dual-specificity kinases that phosphorylate serine/arginine-rich (SR) proteins, a class of regulatory factors that guide the spliceosome — the molecular machine that removes non-coding introns from pre-messenger RNA and joins the remaining exons together. By adding phosphate groups to SR proteins, CLK enzymes control their location within the nucleus and their activity, thereby shaping which splice sites are used and which alternative versions of a gene's message are produced. Because splicing decisions influence the abundance and identity of thousands of proteins, cells that are under high proliferative or transcriptional stress, such as many cancer cells, often become unusually dependent on efficient, well-tuned splicing to sustain their growth programs. Inhibiting CLK activity disrupts this fine control, producing aberrant splicing events, such as retained introns or exon skipping, that can degrade or misregulate transcripts the cell needs to survive. This creates a rationale for using CLK inhibitors to selectively stress malignant cells that have built a dependency on high splicing output, particularly in blood cancers and other tumors driven by strong oncogenic transcriptional activity. The approach represents one arm of a broader interest in modulating RNA splicing as a druggable process in oncology.