This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
2h8h
From Proteopedia
(New page: 200px<br /> <applet load="2h8h" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h8h, resolution 2.20Å" /> '''Src kinase in compl...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2h8h.gif|left|200px]]<br /> | + | [[Image:2h8h.gif|left|200px]]<br /><applet load="2h8h" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2h8h" size=" | + | |
caption="2h8h, resolution 2.20Å" /> | caption="2h8h, resolution 2.20Å" /> | ||
'''Src kinase in complex with a quinazoline inhibitor'''<br /> | '''Src kinase in complex with a quinazoline inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Src family kinases (SFKs) are nonreceptor tyrosine kinases that are | + | 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== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 2H8H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with H8H as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http:// | + | 2H8H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=H8H:'>H8H</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H8H OCA]. |
==Reference== | ==Reference== | ||
| Line 20: | Line 19: | ||
[[Category: Breed, J.]] | [[Category: Breed, J.]] | ||
[[Category: Norman, R.]] | [[Category: Norman, R.]] | ||
| - | [[Category: Otterbein, L | + | [[Category: Otterbein, L R.]] |
| - | [[Category: Pauptit, R | + | [[Category: Pauptit, R A.]] |
[[Category: Rowsell, S.]] | [[Category: Rowsell, S.]] | ||
[[Category: H8H]] | [[Category: H8H]] | ||
[[Category: src kinase]] | [[Category: src kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:39:20 2008'' |
Revision as of 15:39, 21 February 2008
|
Src kinase in complex with a quinazoline inhibitor
Contents |
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 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
Page seeded by OCA on Thu Feb 21 17:39:20 2008
