1YW9

h-MetAP2 complexed with A849519

Summary for 1YW9

• Entry DOI: 10.2210/pdb1yw9/pdb
• Related: 1YW7 1YW8
• Descriptor: Methionine aminopeptidase 2, MANGANESE (II) ION, 2-[({2-[(1Z)-3-(DIMETHYLAMINO)PROP-1-ENYL]-4-FLUOROPHENYL}SULFONYL)AMINO]-5,6,7,8-TETRAHYDRONAPHTHALENE-1-CARBOXYLIC ACID, ... (4 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41912.39

Authors

Park, C.H. (deposition date: 2005-02-17, release date: 2006-02-21, Last modification date: 2011-07-13)

Primary citation

Sheppard, G.S.,Wang, J.,Kawai, M.,Fidanze, S.D.,BaMaung, N.Y.,Erickson, S.A.,Barnes, D.M.,Tedrow, J.S.,Kolaczkowski, L.,Vasudevan, A.,Park, D.C.,Wang, G.T.,Sanders, W.J.,Mantei, R.A.,Palazzo, F.,Tucker-Garcia, L.,Lou, P.,Zhang, Q.,Park, C.H.,Kim, K.H.,Petros, A.,Olejniczak, E.,Nettesheim, D.,Hajduk, P.,Henkin, J.,Lesniewski, R.,Davidsen, S.K.,Bell, R.L.
Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.
J.Med.Chem., 49:3832-3849, 2006

PubMed Abstract: Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.

PubMed: 16789740
DOI: 10.1021/jm0601001

Experimental method

X-RAY DIFFRACTION (1.64 Å)