Dianilinophthalimides: potent and selective, ATP-competitive inhibitors of the EGF-receptor protein tyrosine kinase
| Autor: | Elisabeth Buchdunger, Thomas F. Meyer, Wilhelm Kump, Rihs G, Marcel Muller, Helmut Mett, Pascal Furet, Urs Regenass, Uwe Trinks, Nicholas B. Lydon |
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| Rok vydání: | 1994 |
| Předmět: |
Antineoplastic Agents
Phthalimides Binding Competitive Mice Structure-Activity Relationship Adenosine Triphosphate Drug Discovery medicine Tumor Cells Cultured Staurosporine Animals Humans RNA Messenger Tyrosine Phosphorylation Protein kinase A Cells Cultured Mice Inbred BALB C biology Kinase Chemistry Autophosphorylation Biological activity 3T3 Cells ErbB Receptors Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Female Drug Screening Assays Antitumor Tyrosine kinase Proto-Oncogene Proteins c-fos medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 37(7) |
| ISSN: | 0022-2623 |
| Popis: | Dianilinophthalimides represent a novel class of inhibitors of the EGF-receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. Steady-state kinetic analysis of compound 3, which showed potent inhibitory activity, revealed competitive type kinetics relative to ATP. Despite a highly symmetrical structure of compound 3, X-ray studies revealed an unsymmetrical propeller-shaped conformation of the molecule which differs clearly from that of the constitutionally related staurosporine aglycons. These conformational differences may explain the reversal of the selectivity profile of compound 3 relative to the staurosporine aglycons. In cellular assays compounds 3 and 4 have been shown to inhibit EGF-induced receptor autophosphorylation, c-fos induction and EGF-dependent proliferation of Balb/c MK cells. This inhibition was selective as compounds had no effect on PDGF-induced receptor autophosphorylation and c-fos induction. Furthermore, compound 3 showed potent antitumor activity in vivo at well-tolerated doses. |
| Databáze: | OpenAIRE |
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