title: Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src.
abstract: Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I.S.E. La Pompelle B.P.1050, 51689 Reims Cedex 2, France. patrick.ple@astrazeneca.com
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Plé
authors.forename: Tim P
authors.initials: TP
authors.lastname: Green
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Hennequin
authors.forename: Jon
authors.initials: J
authors.lastname: Curwen
authors.forename: Michael
authors.initials: M
authors.lastname: Fennell
authors.forename: Jack
authors.initials: J
authors.lastname: Allen
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert-Van Der Brempt
authors.forename: Gerard
authors.initials: G
authors.lastname: Costello
mesh_terms: D016475:3T3 Cells; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D004149:Dioxoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004149:Dioxoles; D011799:Quinazolines; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases