2h8h

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Revision as of 20:21, 12 November 2007

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spinqualitylabelsall models 2h8h, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Src kinase in complex with a quinazoline inhibitor

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known disease associated with this structure: Colon cancer, advanced OMIM:[190090]

About this Structure

2H8H is a Single protein structure of sequence from Homo sapiens with H8H as ligand. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.

Reference

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., Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, Lambert-van der Brempt C, Morgentin R, Norman RA, Olivier A, Otterbein L, Ple PA, Warin N, Costello G, J Med Chem. 2006 Nov 2;49(22):6465-88. PMID:17064066

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