Inhibition of wild type NPM/ALK autophosphorylation activity in BaF3 cells by antiphosphotyrosine immunoblotting assay
- Deposit:2010-05-25
- Modify:2020-07-03
Title: Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and homology modeling.
Abstract: Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inhibition studies, and molecular modeling. Mutation of the gatekeeper residue, a key structural determinant influencing inhibitor binding, rendered the fusion protein, NPM/ALK, sensitive to inhibition by SKI-606 in the nanomolar range, while PD173955 inhibited the NPM/ALK mutant at micromolar concentrations. In contrast, both wild type and mutant NPM/ALK were insensitive to imatinib. Computer modeling indicated that docking solutions obtained with a homology model representing the intermediate conformation of the ALK kinase domain reflected closely experimental data. The good agreement between experimental and virtual results indicate that the ALK molecular models described here are useful tools for the rational design of ALK selective inhibitors. In addition, 4-phenylamino-quinoline compounds may have potential as templates for ALK inhibitors.
Journal: J Med Chem
Year: 2006
Volume: 49
Issue: 19
First Page: 5759
Last Page: 5768
DOI: 10.1021/jm060380k
Target ChEMBL ID: CHEMBL2111387
ChEMBL Target Name: NPM/ALK (Nucleophosmin/ALK tyrosine kinase receptor)
ChEMBL Target Type: CHIMERIC PROTEIN - Target is a fusion of two different proteins, either a synthetic construct or naturally occurring fusion protein
Relationship Type: D - Direct protein target assigned
Confidence: Direct protein complex subunits assigned
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