2H8H

Src kinase in complex with a quinazoline inhibitor

Summary for 2H8H

• Entry DOI: 10.2210/pdb2h8h/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE (3 entities in total)
• Functional Keywords: src kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane: P12931
• Total number of polymer chains: 1
• Total formula weight: 60397.38

Authors

Otterbein, L.R.,Norman, R.,Pauptit, R.A.,Rowsell, S.,Breed, J. (deposition date: 2006-06-07, release date: 2006-11-21, Last modification date: 2024-10-30)

Primary citation

Hennequin, L.F.,Allen, J.,Breed, J.,Curwen, J.,Fennell, M.,Green, T.P.,Lambert-van der Brempt, C.,Morgentin, R.,Norman, R.A.,Olivier, A.,Otterbein, L.,Ple, P.A.,Warin, N.,Costello, G.
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.
J.Med.Chem., 49:6465-6488, 2006

PubMed 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.

PubMed: 17064066
DOI: 10.1021/jm060434q

Experimental method

X-RAY DIFFRACTION (2.2 Å)