PDBsum entry 2h8h

Transferase

PDB id: 2h8h

Contents

Protein chain

445 a.a.

Ligands

H8H

Waters ×221

References listed in PDB file

Key reference

• 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.
• Authors: L.F.Hennequin, J.Allen, J.Breed, J.Curwen, M.Fennell, T.P.Green, C.Lambert-Van der brempt, R.Morgentin, R.A.Norman, A.Olivier, L.Otterbein, P.A.Plé, N.Warin, G.Costello.
• Ref.: J Med Chem, 2006, 49, 6465-6488. [DOI no: 10.1021/jm060434q]
• PubMed id: 17064066

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.