Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure.
The extracellular signal-regulated kinases (ERK1 and ERK2) are important mediators of cell proliferation. Constitutive activation of the ERK proteins plays a critical role in the proliferation of many human cancers. Taking advantage of recently identified substrate docking domains on ERK2, we have used computer-aided drug design (CADD) to identify novel low molecular weight compounds that interact with ERK2 in an ATP-independent manner and disrupt substrate-specific interactions. In the current study, a CADD screen of the 3D structure of active phosphorylated ERK2 protein was used to identify inhibitory compounds. We tested 13 compounds identified by the CADD screen in ERK-specific phosphorylation, cell proliferation, and binding assays. Of the 13 compounds tested, 4 compounds strongly inhibited ERK-mediated phosphorylation of ribosomal S6 kinase-1 (Rsk-1) and/or the transcription factor Elk-1 and inhibited the proliferation of HeLa cervical carcinoma cells with IC(50) values in the 2-10 microM range. These studies demonstrate that CADD can be used to identify lead compounds for development of novel non-ATP-dependent inhibitors selective for active ERK and its interactions with substrates involved in cancer cell proliferation.
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- Protein Kinase Inhibitors
- Protein Conformation
- Models, Molecular
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 1
- Medicinal & Biomolecular Chemistry
- Kinetics
- Binding Sites
- Adenosine Triphosphate
- 3405 Organic chemistry
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Protein Kinase Inhibitors
- Protein Conformation
- Models, Molecular
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 1
- Medicinal & Biomolecular Chemistry
- Kinetics
- Binding Sites
- Adenosine Triphosphate
- 3405 Organic chemistry