Dianilinophthalimides: Potent and Selective, ATP-Competitive Inhibitors of the EGF-Receptor Protein Tyrosine Kinase

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 typ...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-04, Vol.37 (7), p.1015-1027
Main Authors: Trinks, Uwe, Buchdunger, Elisabeth, Furet, Pascal, Kump, Wilhelm, Mett, Helmut, Meyer, Thomas, Mueller, Marcel, Regenass, Urs, Rihs, Greti
Format: Article
Language:English
Subjects:
3T3 Cells
Adenosine Triphosphate - metabolism
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Binding, Competitive
Cells, Cultured
Chemistry
Drug Screening Assays, Antitumor
ErbB Receptors - antagonists & inhibitors
Exact sciences and technology
Female
Heterocyclic compounds
Heterocyclic compounds with only one n hetero atom and condensed derivatives
Humans
Mice
Mice, Inbred BALB C
Organic chemistry
Phosphorylation
Phthalimides - chemical synthesis
Phthalimides - pharmacology
Preparations and properties
Proto-Oncogene Proteins c-fos - genetics
RNA, Messenger - metabolism
Structure-Activity Relationship
Tumor Cells, Cultured
Tyrosine - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00033a019