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rdf:type |
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lifeskim:mentions |
umls-concept:C0001924,
umls-concept:C0025646,
umls-concept:C0038760,
umls-concept:C0051959,
umls-concept:C0243077,
umls-concept:C0301630,
umls-concept:C0678594,
umls-concept:C1167622,
umls-concept:C1527178,
umls-concept:C1880355,
umls-concept:C2698650
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pubmed:issue |
13
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pubmed:dateCreated |
2006-6-22
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BaMaungNwe YNY,
pubmed-author:BarnesDavid MDM,
pubmed-author:BellRandy LRL,
pubmed-author:DavidsenSteven KSK,
pubmed-author:EricksonScott ASA,
pubmed-author:FidanzeSteve DSD,
pubmed-author:HajdukPhillipP,
pubmed-author:HenkinJackJ,
pubmed-author:KawaiMegumiM,
pubmed-author:KayaH OHO,
pubmed-author:KolaczkowskiLawrenceL,
pubmed-author:LesniewskiRichardR,
pubmed-author:LouPingpingP,
pubmed-author:ManteiRobert ARA,
pubmed-author:NettesheimDavidD,
pubmed-author:OlejniczakEdwardE,
pubmed-author:PalazzoFabioF,
pubmed-author:ParkChang HCH,
pubmed-author:ParkDavid CDC,
pubmed-author:PetrovAndrejA,
pubmed-author:SandersWilliam JWJ,
pubmed-author:SheppardGeorge SGS,
pubmed-author:TedrowJason SJS,
pubmed-author:Tucker-GarciaLoraL,
pubmed-author:VasudevanAnilA,
pubmed-author:WangGary TGT,
pubmed-author:WangJieyiJ,
pubmed-author:ZhangQianQ
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pubmed:issnType |
Print
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pubmed:day |
29
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3832-49
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:16789740-Aminopeptidases,
pubmed-meshheading:16789740-Animals,
pubmed-meshheading:16789740-Anthranilic Acids,
pubmed-meshheading:16789740-Antineoplastic Agents,
pubmed-meshheading:16789740-Cell Line, Tumor,
pubmed-meshheading:16789740-Cell Proliferation,
pubmed-meshheading:16789740-Humans,
pubmed-meshheading:16789740-Mass Spectrometry,
pubmed-meshheading:16789740-Metalloendopeptidases,
pubmed-meshheading:16789740-Methionine,
pubmed-meshheading:16789740-Models, Molecular,
pubmed-meshheading:16789740-Protein Binding,
pubmed-meshheading:16789740-Protein Conformation,
pubmed-meshheading:16789740-Protein Structure, Tertiary,
pubmed-meshheading:16789740-Rats,
pubmed-meshheading:16789740-Serum Albumin,
pubmed-meshheading:16789740-Structure-Activity Relationship,
pubmed-meshheading:16789740-Sulfonamides
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pubmed:year |
2006
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pubmed:articleTitle |
Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.
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pubmed:affiliation |
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Department R47A, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. george.s.sheppard@abbott.com
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pubmed:publicationType |
Journal Article,
In Vitro
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