2OAZ

Human Methionine Aminopeptidase-2 Complexed with SB-587094

Summary for 2OAZ

• Entry DOI: 10.2210/pdb2oaz/pdb
• Descriptor: human Methionine Amino Peptidase 2, COBALT (II) ION, N-(2-ISOPROPYLPHENYL)-3-[(2-THIENYLMETHYL)THIO]-1H-1,2,4-TRIAZOL-5-AMINE, ... (4 entities in total)
• Functional Keywords: metap2, methionine, amino peptidase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41818.34

Authors

Marino Jr., J.P.,Fisher, P.W.,Hofmann, G.A.,Kirkpatrick, R.,Janson, C.A.,Johnson, R.K.,Ma, C.,Mattern, M.,Meek, T.D.,Ryan, D.,Schulz, C.,Smith, W.W.,Tew, D.G.,Tomazek Jr., T.A.,Veber, D.F.,Xiong, W.C.,Yamamoto, Y.,Yamashita, K.,Yang, G.,Thompson, S.K. (deposition date: 2006-12-18, release date: 2007-06-19, Last modification date: 2024-11-20)

Primary citation

Marino, J.P.,Fisher, P.W.,Hofmann, G.A.,Kirkpatrick, R.B.,Janson, C.A.,Johnson, R.K.,Ma, C.,Mattern, M.,Meek, T.D.,Ryan, M.D.,Schulz, C.,Smith, W.W.,Tew, D.G.,Tomazek, T.A.,Veber, D.F.,Xiong, W.C.,Yamamoto, Y.,Yamashita, K.,Yang, G.,Thompson, S.K.
Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore.
J.Med.Chem., 50:3777-3785, 2007

PubMed Abstract: 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.

PubMed: 17636946
DOI: 10.1021/jm061182w

Experimental method

X-RAY DIFFRACTION (1.9 Å)