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| [[Image:2oaz.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2oaz| PDB=2oaz | SCENE= }} | | {{STRUCTURE_2oaz| PDB=2oaz | SCENE= }} |
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| '''Human Methionine Aminopeptidase-2 Complexed with SB-587094'''
| | ===Human Methionine Aminopeptidase-2 Complexed with SB-587094=== |
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| ==Overview==
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| High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17636946}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17636946 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17636946}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Metap2]] | | [[Category: Metap2]] |
| [[Category: Methionine]] | | [[Category: Methionine]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:32:20 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 15:33:34 2008'' |