Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs
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Ewelina Węglarz-Tomczak1,2, Michał Talma1, Mirosław Giurg3, Hans V. Westerhoff2, Robert Janowski4 and Artur Mucha1
1Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wrocław, Poland
2Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands
3Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wrocław, Poland
4Institute of Structural Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
Ewelina Węglarz-Tomczak, email: [email protected]
Keywords: metalloaminopeptidases; cancer; actinomycin D; phenoxazones; biological activity
Received: November 11, 2017 Accepted: May 14, 2018 Published: June 29, 2018
The potent transcription inhibitor Actinomycin D is used with several cancers. Here, we report the discovery that this naturally occurring antibiotic inhibits two human neutral aminopeptidases, the cell-surface alanine aminopeptidase and intracellular methionine aminopeptidase type 2. These metallo-containing exopeptidases participate in tumor cell expansion and motility and are targets for anticancer therapies. We show that the peptide portions of Actinomycin D and Actinomycin X2 are not required for effective inhibition, but the loss of these regions changes the mechanism of interaction. Two structurally less complex Actinomycin D analogs containing the phenoxazone chromophores, Questiomycin A and Actinocin, appear to be competitive inhibitors of both aminopeptidases, with potencies similar to the non-competitive macrocyclic parent compound (Ki in the micromolar range). The mode of action for all four compounds and both enzymes was demonstrated by molecular modeling and docking in the corresponding active sites. This knowledge gives new perspectives to Actinomycin D’s action on tumors and suggests new avenues and molecules for medical applications.
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