title: Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases.
abstract: We identified and characterized β-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. β-Aminoketones with certain structural features form α,β-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms. The initially identified tetralone derivatives showed complete selectivity for E. coli MetAP versus human MetAP-1 and MetAP-2. Rational design of indanone analogs yielded compounds with selectivity for the human type-1 versus the human type-2 MetAP.
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Altmeyer
authors.affiliation: Präklinische Targetentwicklung, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Amtmann
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Heyl
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Marschner
authors.affiliation: Zoological Institute, Department of Structural Biology, Kiel University, Am Botanischen Garten 1-9, 24118 Kiel, Germany.
authors.forename: Axel J
authors.initials: AJ
authors.lastname: Scheidig
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany. Electronic address: c.klein@uni-heidelberg.de.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000378:metabolism; D063208:Methionyl Aminopeptidases; D062105:Molecular Docking Simulation; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007659:Ketones; D011355:Prodrugs; D000626:Aminopeptidases; C506619:METAP1 protein, human; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases
keywords: Beta-aminoketone; Enzyme inhibition; Irreversible inhibitors; Methionine aminopeptidase; Prodrug