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11:11
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
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Novel non-ATP competitive small molecules targeting the CK2 α/β interface
Paul Brear1, Andrew North2, Jessica Iegre2
1Department of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge CB2 1GA, UK.
Bioorganic & Medicinal Chemistry
|May 16, 2018
Summary
Researchers identified a novel fragment, CAM187, that inhibits the interaction between CK2α and CK2β subunits. This fragment shows promise for developing new cancer therapies targeting casein kinase 2 (CK2) overactivity.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Elevated casein kinase 2 (CK2) levels are common in various cancers.
- CK2 is crucial in numerous cell-signaling pathways, making it a therapeutic target.
- Inhibiting CK2 can impede tumor progression.
Purpose of the Study:
- To develop a fragment-based approach for inhibiting the CK2α/CK2β interaction.
- To identify novel inhibitors targeting the holoenzyme's interface.
Main Methods:
- Fragment-based drug discovery.
- Co-crystallization of fragments with CK2α.
- Biochemical assays to determine inhibitory activity (IC50).
Main Results:
- Identified fragment CAM187 with an IC50 of 44 μM and molecular weight of 257 g/mol.
- CAM187 selectively binds to the CK2α/CK2β interface, not the ATP binding site.
- Fragment-like molecules represent novel scaffolds for CK2 inhibition.
Conclusions:
- Fragment CAM187 is a promising lead for developing CK2 inhibitors.
- Targeting the α-β interface offers a unique strategy for CK2-based cancer therapy.
- Further optimization of these scaffolds can lead to potent therapeutic agents.
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