2oaz: Difference between revisions

Revision as of 19:16, 21 February 2008

Human Methionine Aminopeptidase-2 Complexed with SB-587094

OverviewOverview

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.

About this StructureAbout this Structure

2OAZ is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Methionyl aminopeptidase, with EC number 3.4.11.18 Full crystallographic information is available from OCA.

ReferenceReference

Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore., Marino JP Jr, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, Ma C, Mattern M, Meek TD, Ryan MD, Schulz C, Smith WW, Tew DG, Tomazek TA Jr, Veber DF, Xiong WC, Yamamoto Y, Yamashita K, Yang G, Thompson SK, J Med Chem. 2007 Aug 9;50(16):3777-85. Epub 2007 Jul 18. PMID:17636946

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 ==Overview==
-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.
+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.
 ==About this Structure==
@@ Line 14: / Line 14: @@
 [[Category: Methionyl aminopeptidase]]
 [[Category: Single protein]]
-[[Category: Fisher, P.W.]]
+[[Category: Fisher, P W.]]
-[[Category: Hofmann, G.A.]]
+[[Category: Hofmann, G A.]]
-[[Category: Janson, C.A.]]
+[[Category: Janson, C A.]]
-[[Category: Johnson, R.K.]]
+[[Category: Johnson, R K.]]
-[[Category: Jr., J.P.Marino.]]
+[[Category: Jr., J P.Marino.]]
-[[Category: Jr., T.A.Tomazek.]]
+[[Category: Jr., T A.Tomazek.]]
 [[Category: Kirkpatrick, R.]]
 [[Category: Ma, C.]]
 [[Category: Mattern, M.]]
-[[Category: Meek, T.D.]]
+[[Category: Meek, T D.]]
 [[Category: Ryan, D.]]
 [[Category: Schulz, C.]]
-[[Category: Smith, W.W.]]
+[[Category: Smith, W W.]]
-[[Category: Tew, D.G.]]
+[[Category: Tew, D G.]]
-[[Category: Thompson, S.K.]]
+[[Category: Thompson, S K.]]
-[[Category: Veber, D.F.]]
+[[Category: Veber, D F.]]
-[[Category: Xiong, W.C.]]
+[[Category: Xiong, W C.]]
 [[Category: Yamamoto, Y.]]
 [[Category: Yamashita, K.]]
@@ Line 41: / Line 41: @@
 [[Category: methionine]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 10:41:45 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:16:29 2008''