Structural Insights into the ATP Binding Pocket of the Anaplastic Lymphoma Kinase by Site-Directed Mutagenesis, Inhibitor Binding Analysis, and Homology Modeling

Article Article scientifique Article Structural Insights into the ATP Binding Pocket of the Anaplastic Lymphoma Kinase by Site-Directed Mutagenesis, Inhibitor Binding Analysis, and Homology Modeling eng 2006-08-23 2006-08-23 author Gunby Rosalind H. author Ahmed Shaheen 624758 author Sottocornola Roberta author Gasser Marc 618778 author Redaelli Sara author Mologni Luca author Tartari Carmen J author Belloni Valentina author Gambacorti-Passerini Carlo author Scapozza Leonardo 600318 5759-5768 10.1021/jm060380k 16970400 0022-2623 https://pubs.acs.org/doi/10.1021/jm060380k 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. Dewey 615 31 Section des sciences pharmaceutiques 17 false Journal of medicinal chemistry 49 19 d70602d2-4757-4ce4-bc92-d27dcfc1d612 Article (Published version) Restricted Article-scientifique-from-crossref.pdf 918499 application/pdf Vignette Public images_medium_jm060380kn00001.gif 37714 image/gif restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques

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Structural Insights into the ATP Binding Pocket of the Anaplastic Lymphoma Kinase by Site-Directed Mutagenesis, Inhibitor Binding Analysis, and Homology Modeling	Journal of medicinal chemistry			2006	138	0

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Gasser, Marc