2p4i
From Proteopedia
(New page: 200px<br /> <applet load="2p4i" size="450" color="white" frame="true" align="right" spinBox="true" caption="2p4i, resolution 2.50Å" /> '''Evolution of a high...) |
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| - | [[Image:2p4i.gif|left|200px]]<br /> | + | [[Image:2p4i.gif|left|200px]]<br /><applet load="2p4i" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2p4i" size=" | + | |
caption="2p4i, resolution 2.50Å" /> | caption="2p4i, resolution 2.50Å" /> | ||
'''Evolution of a highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor'''<br /> | '''Evolution of a highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor'''<br /> | ||
| - | == | + | ==Overview== |
| - | + | Inhibition of angiogenesis is a promising and clinically validated, approach for limiting tumor growth and survival. The receptor tyrosine, kinase Tie-2 is expressed almost exclusively in the vascular endothelium, and is required for developmental angiogenesis and vessel maturation., However, the significance of Tie-2 signaling in tumor angiogenesis is not, well understood. In order to evaluate the therapeutic utility of, inhibiting Tie-2 signaling, we developed a series of potent and orally, bioavailable small molecule Tie-2 kinase inhibitors with selectivity over, other kinases, especially those that are believed to be important for, tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a, potent, nonselective Tie-2 inhibitor that was designed on the basis of, X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35, (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which, exhibited >30-fold selectivity over a panel of kinases, good oral, exposure, and in vivo inhibition of Tie-2 phosphorylation. | |
==About this Structure== | ==About this Structure== | ||
| - | 2P4I 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 MR9 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http:// | + | 2P4I 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=MR9:'>MR9</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P4I OCA]. |
| + | |||
| + | ==Reference== | ||
| + | Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine tie-2 kinase inhibitor., Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, Zhao H, J Med Chem. 2007 Feb 22;50(4):611-26. Epub 2007 Jan 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17253678 17253678] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Receptor protein-tyrosine kinase]] | [[Category: Receptor protein-tyrosine kinase]] | ||
| Line 15: | Line 17: | ||
[[Category: MR9]] | [[Category: MR9]] | ||
[[Category: tie-2 kinase inhibitor triazine]] | [[Category: tie-2 kinase inhibitor triazine]] | ||
| + | [[Category: transferase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:04:30 2008'' |
Revision as of 10:04, 23 January 2008
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Evolution of a highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor
Overview
Inhibition of angiogenesis is a promising and clinically validated, approach for limiting tumor growth and survival. The receptor tyrosine, kinase Tie-2 is expressed almost exclusively in the vascular endothelium, and is required for developmental angiogenesis and vessel maturation., However, the significance of Tie-2 signaling in tumor angiogenesis is not, well understood. In order to evaluate the therapeutic utility of, inhibiting Tie-2 signaling, we developed a series of potent and orally, bioavailable small molecule Tie-2 kinase inhibitors with selectivity over, other kinases, especially those that are believed to be important for, tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a, potent, nonselective Tie-2 inhibitor that was designed on the basis of, X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35, (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which, exhibited >30-fold selectivity over a panel of kinases, good oral, exposure, and in vivo inhibition of Tie-2 phosphorylation.
About this Structure
2P4I is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Full crystallographic information is available from OCA.
Reference
Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine tie-2 kinase inhibitor., Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, Zhao H, J Med Chem. 2007 Feb 22;50(4):611-26. Epub 2007 Jan 25. PMID:17253678
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