SGC-CLK-1: A chemical probe for the Cdc2-like kinases CLK1, CLK2, and CLK4.

Small molecule modulators are important tools to study both basic biology and the complex signaling of protein kinases. The cdc2-like kinases (CLK) are a family of four kinases that have garnered recent interest for their involvement in a diverse set of diseases such as neurodegeneration, autoimmunity, and many cancers. Targeted medicinal chemistry around a CLK inhibitor hit identified through screening of a kinase inhibitor set against a large panel of kinases allowed us to identify a potent and selective inhibitor of CLK1, 2, and 4. Here, we present the synthesis, selectivity, and preliminary biological characterization of this compound - SGC-CLK-1 (CAF-170). We further show CLK2 has the highest binding affinity, and high CLK2 expression correlates with a lower IC50 in a screen of multiple cancer cell lines. Finally, we show that SGC-CLK-1 not only reduces serine arginine-rich (SR) protein phosphorylation but also alters SR protein and CLK2 subcellular localization in a reversible way. Therefore, we anticipate that this compound will be a valuable tool for increasing our understanding of CLKs and their targets, SR proteins, at the level of phosphorylation and subcellular localization.

Citation

Deanna Tiek, Carrow I Wells, Martin Schröder, Xiao Song, Carla Alamillo-Ferrer, Anshika Goenka, Rebeca Iglesia, Minghui Lu, Bo Hu, Frank Kwarcinski, Parvathi Sintha, Chandi de Silva, Mohammad Anwar Hossain, Alfredo Picado, William Zuercher, Reena Zutshi, Stefan Knapp, Rebecca B Riggins, Shi-Yuan Cheng, David H Drewry. SGC-CLK-1: A chemical probe for the Cdc2-like kinases CLK1, CLK2, and CLK4. Current research in chemical biology. 2023;3

PMID: 38009092

search → result