title: N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor.
abstract: Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.
authors.affiliation: Centre de Recherches, AstraZeneca, ZISE La Pompelle, B.P. 1050, 51689 Reims Cedex 2, France. Laurent.hennequin@astrazeneca.com
authors.forename: Laurent F
authors.initials: LF
authors.lastname: Hennequin
authors.forename: Jack
authors.initials: J
authors.lastname: Allen
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.forename: Jon
authors.initials: J
authors.lastname: Curwen
authors.forename: Michael
authors.initials: M
authors.lastname: Fennell
authors.forename: Tim P
authors.initials: TP
authors.lastname: Green
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert-van der Brempt
authors.forename: Rémy
authors.initials: R
authors.lastname: Morgentin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Norman
authors.forename: Annie
authors.initials: A
authors.lastname: Olivier
authors.forename: Ludovic
authors.initials: L
authors.lastname: Otterbein
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Plé
authors.forename: Nicolas
authors.initials: N
authors.lastname: Warin
authors.forename: Gerard
authors.initials: G
authors.lastname: Costello
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D052117:Benzodioxoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011799:Quinazolines; C515233:saracatinib; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases