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 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.
Trinks
U
U
Oncology and Virology Research Department, Ciba-Geigy Limited, Basel, Switzerland.
Buchdunger
E
E
Furet
P
P
Kump
W
W
Mett
H
H
Meyer
T
T
Müller
M
M
Regenass
U
U
Rihs
G
G
Lydon
N
N
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D010797:Phthalimides / Q000138:chemical synthesis / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D010797:Phthalimides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014443:Tyrosine; D000255:Adenosine Triphosphate; D066246:ErbB Receptors