Development of Cdc2-like Kinase 2 Inhibitors: Achievements and Future Directions.

Cdc2-like kinases (CLKs; CLK1-4) are associated with various neurodegenerative disorders, metabolic regulation, and viral infection and have been recognized as potential drug targets. Human CLK2 has received increasing attention as a regulator that phosphorylates serine- and arginine-rich (SR) proteins and subsequently modulates the alternative splicing of precursor mRNA (pre-mRNA), which is an attractive target for degenerative disease and cancer. Numerous CLK2 inhibitors have been identified, with several molecules currently in clinical development. The first CLK2 inhibitor Lorecivivint (compound 1) has recently entered phase 3 clinical trials. However, highly selective CLK2 inhibitors are rarely reported. This Perspective summarizes the biological roles and therapeutic potential of CLK2 along with progress on the development of CLK2 inhibitors and discusses the achievements and future prospects of CLK2 inhibitors for therapeutic applications.