1pxm
From Proteopedia
(New page: 200px<br /> <applet load="1pxm" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pxm, resolution 2.53Å" /> '''HUMAN CYCLIN DEPEND...) |
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| - | [[Image:1pxm.gif|left|200px]]<br /> | + | [[Image:1pxm.gif|left|200px]]<br /><applet load="1pxm" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1pxm" size=" | + | |
caption="1pxm, resolution 2.53Å" /> | caption="1pxm, resolution 2.53Å" /> | ||
'''HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR 3-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenol'''<br /> | '''HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR 3-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenol'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Following the identification through virtual screening of | + | Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition. |
==About this Structure== | ==About this Structure== | ||
| - | 1PXM 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 CK5 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1PXM 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=CK5:'>CK5</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PXM OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Anderson, S.]] | [[Category: Anderson, S.]] | ||
| - | [[Category: Fischer, P | + | [[Category: Fischer, P M.]] |
[[Category: Griffiths, G.]] | [[Category: Griffiths, G.]] | ||
[[Category: Jackson, W.]] | [[Category: Jackson, W.]] | ||
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[[Category: Osnowski, A.]] | [[Category: Osnowski, A.]] | ||
[[Category: Thomas, M.]] | [[Category: Thomas, M.]] | ||
| - | [[Category: Walkinshaw, M | + | [[Category: Walkinshaw, M D.]] |
[[Category: Wang, S.]] | [[Category: Wang, S.]] | ||
[[Category: Wood, G.]] | [[Category: Wood, G.]] | ||
| - | [[Category: Wu, S | + | [[Category: Wu, S Y.]] |
[[Category: Yuill, R.]] | [[Category: Yuill, R.]] | ||
[[Category: Zheleva, D.]] | [[Category: Zheleva, D.]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:33:36 2008'' |
Revision as of 12:33, 21 February 2008
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HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR 3-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenol
Overview
Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.
About this Structure
1PXM is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity., Wang S, Meades C, Wood G, Osnowski A, Anderson S, Yuill R, Thomas M, Mezna M, Jackson W, Midgley C, Griffiths G, Fleming I, Green S, McNae I, Wu SY, McInnes C, Zheleva D, Walkinshaw MD, Fischer PM, J Med Chem. 2004 Mar 25;47(7):1662-75. PMID:15027857
Page seeded by OCA on Thu Feb 21 14:33:36 2008
Categories: Homo sapiens | Single protein | Anderson, S. | Fischer, P M. | Griffiths, G. | Jackson, W. | McInnes, C. | McNae, I. | Meades, C. | Midgley, C. | Osnowski, A. | Thomas, M. | Walkinshaw, M D. | Wang, S. | Wood, G. | Wu, S Y. | Yuill, R. | Zheleva, D. | CK5 | 3d-structure. | Atp-binding | Cell cycle | Cell division | Inhibition | Mitosis | Phosphorylation | Protein kinase | Serine/threonine-protein kinase | Transferase
