Tiek Deanna, Wells Carrow I, Schröder Martin, Song Xiao, Alamillo-Ferrer Carla, Goenka Anshika, Iglesia Rebeca, Lu Minghui, Hu Bo, Kwarcinski Frank, Sintha Parvathi, de Silva Chandi, Hossain Mohammad Anwar, Picado Alfredo, Zuercher William, Zutshi Reena, Knapp Stefan, Riggins Rebecca B, Cheng Shi-Yuan, Drewry David H
The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Curr Res Chem Biol. 2023;3. doi: 10.1016/j.crchbi.2023.100045. Epub 2023 Sep 22.
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 IC 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.
小分子调节剂是研究基础生物学和蛋白激酶复杂信号传导的重要工具。细胞周期蛋白依赖性激酶2样激酶（CLK）是一个由四种激酶组成的家族，最近因其参与多种疾病（如神经退行性变、自身免疫和许多癌症）而受到关注。通过针对大量激酶筛选激酶抑制剂集鉴定出一种CLK抑制剂先导化合物后，开展靶向药物化学研究，使我们能够鉴定出一种对CLK1、2和4具有强效和选择性的抑制剂。在此，我们介绍该化合物SGC-CLK-1（CAF-170）的合成、选择性和初步生物学特性。我们进一步表明，CLK2具有最高的结合亲和力，并且在多个癌细胞系的筛选中，高CLK2表达与较低的半数抑制浓度相关。最后，我们表明SGC-CLK-1不仅降低富含丝氨酸精氨酸（SR）蛋白的磷酸化，还以可逆方式改变SR蛋白和CLK2的亚细胞定位。因此，我们预计该化合物将成为一个有价值的工具，有助于我们在磷酸化和亚细胞定位水平上增进对CLK及其靶点SR蛋白的理解。
