Small Molecule Inhibitors Targeting Cdc2‐Like Kinase 4: Advances, Challenges, and Opportunities

ABSTRACT Cdc2‐like kinase 4 (Clk4), a key member of the CMGC kinase family, plays a crucial role in alternative splicing, which profoundly influences various physiological processes, including cellular signaling, proliferation, and survival. Its involvement in these vital functions has positioned Clk4 as an important target for therapeutic intervention in a range of diseases, such as neurodegenerative disorders, viral and parasitic infections, and cancer. This review highlights recent advancements in Clk4 inhibitors, covering both natural, and synthetic compounds. It further examines the core scaffolds and essential functional groups of Clk4 small‐molecule inhibitors, emphasizing the most promising chemical structures. Additionally, the review explores the structure–activity relationships (SARs) and molecular binding modes of existing Clk4 inhibitors, offering insights and strategies for the development of novel Clk4‐targeted drugs. This review highlights recent advancements in small molecule inhibitors targeting Clk4, emphasizing their potential in treating cancers and neurodegenerative diseases. It explores SARs, binding modes, and challenges in developing selective Clk4 inhibitors, offering insights for future therapeutic strategies.