SGC-CLK-1 (CAF-170) a chemical probe for the Cdc2-Like kinases CLK1, CLK2, and CLK4
Tiek, D.; Wells, C. I.; Schroder, M.; Song, X.; Ferrer, C. A.; Goenka, A.; Iglesia, R.; Lu, M.; Hu, B.; Kwarcinski, F.; Sintha, P.; de Silva, C.; Hossain, M. A.; Picado, A.; Zuercher, W.; Zutshi, R.; Knapp, S.; Riggins, R. B.; Cheng, S.; Drewry, D.
Show abstract
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 potential binding site of this compound - SGC-CLK-1. 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.
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