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

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

  • Curr Res Chem Biol. 2023:3:100045. doi: 10.1016/j.crchbi.2023.100045.
Deanna Tiek 1,  Carrow I Wells 2,  Martin Schröder 3 4,  Xiao Song 1,  Carla Alamillo-Ferrer 2,  Anshika Goenka 1,  Rebeca Iglesia 1,  Minghui Lu 1,  Bo Hu 1,  Frank Kwarcinski 5,  Parvathi Sintha 5,  Chandi de Silva 5,  Mohammad Anwar Hossain 2,  Alfredo Picado 2,  William Zuercher 2,  Reena Zutshi 5,  Stefan Knapp 3 4,  Rebecca B Riggins 6,  Shi-Yuan Cheng 1,  David H Drewry 2 7
Affiliations

Affiliations

  • 1 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.
  • 2 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 3 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences (BMLS), Goethe University Frankfurt am Main, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany.
  • 4 Institut für Pharmazeutische Chemie, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, Frankfurt am Main, 60438, Germany.
  • 5 Luceome Biotechnologies LLC, Tucson, AZ, 85719, USA.
  • 6 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA.
  • 7 UNC Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
PMID: 38009092 DOI: 10.1016/j.crchbi.2023.100045
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 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.

Keywords

CLK1; CLK2; CLK4; Chemical probe; Splicing.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153708
    CLK1/2/4 Inhibitor
    CDK