Abstract
We have screened molecules for inhibition of MetAP2 as a novel approach toward antiangiogenesis and anticancer therapy using affinity selection/mass spectrometry (ASMS) employing MetAP2 loaded with Mn(2+) as the active site metal. After a series of anthranilic acid sulfonamides with micromolar affinities was identified, chemistry efforts were initiated. The micromolar hits were quickly improved to potent nanomolar inhibitors by chemical modifications guided by insights from X-ray crystallography.
MeSH terms
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Aminopeptidases / antagonists & inhibitors*
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Binding Sites
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Cell Line
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Glycoproteins / antagonists & inhibitors*
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Humans
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Manganese / chemistry
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Mass Spectrometry / methods
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Methionyl Aminopeptidases
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Models, Molecular
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Molecular Structure
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Sensitivity and Specificity
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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Glycoproteins
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Sulfonamides
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Manganese
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Aminopeptidases
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METAP2 protein, human
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Methionyl Aminopeptidases