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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Irreversible Nek2 kinase inhibitors with cellular activity
Jeffrey C Henise1, Jack Taunton
1Program in Chemistry and Chemical Biology, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, United States.
Journal of Medicinal Chemistry
|June 2, 2011
Summary
Researchers developed a novel small molecule inhibitor targeting the Nek2 kinase. This compound selectively inactivates Nek2 in cells, offering a new tool for studying its function.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Nek2 is a human centrosomal kinase implicated in various cellular processes.
- Targeting kinase activity is a key strategy in drug development.
- Irreversible inhibitors offer prolonged target engagement.
Purpose of the Study:
- To design and characterize novel, selective, irreversible inhibitors of Nek2 kinase.
- To identify a small molecule capable of inactivating Nek2 in a cellular context.
Main Methods:
- Structure-based drug design utilizing an oxindole scaffold.
- Biochemical and cell-based assays to assess kinase inhibition.
- Evaluation of compound selectivity against related kinases (Cdk1, Aurora B, Plk1).
- Assessment of effects on cellular processes like spindle assembly.
Main Results:
- A selective irreversible inhibitor, oxindole propynamide 16 (JH295), was identified.
- Compound 16 potently inhibited Nek2 kinase activity in biochemical and cellular assays.
- 16 demonstrated selectivity, not affecting other key mitotic kinases.
- The compound did not disrupt bipolar spindle assembly or the spindle assembly checkpoint.
- 16 is the first small molecule reported to inactivate Nek2 in cells.
Conclusions:
- Oxindole propynamide 16 represents a significant advancement in targeting Nek2.
- This selective inhibitor provides a valuable chemical probe for investigating Nek2 function.
- The findings open avenues for exploring Nek2's role in health and disease.
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