Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs

Abstract

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.

Synthesis and Structure-Activity Relationship Studies of Hydrazide-Hydrazones as Inhibitors of Laccase from Trametes versicolor

“…Furthermore, we aimed at discovering a new group of organic low-molecular-weight compounds which activity that weakens a pest's activity and consequently provides conditions for improving the plant defense system. The imines 1-3 were synthesized as part of a program to discover low-molecular-weight compounds that were both the inhibitors of essential enzymes overexpressed during disease development [25][26][27] and act directly against pathogenic microorganisms [28,29]. A common polypore fungus Trametes versicolor, which is an abundant tree parasite causing a white-rot of wood, was chosen as a model organism.…”

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

“…Critical relevance of its activity for cancer progression caused intensive studies to be undertaken to develop new drugs directed towards this enzyme, including enzyme inhibitors and APN-targeted carrier constructs [15,16]. As a consequence, a variety of APN inhibitors have been developed [17][18][19][20][21][22][23].…”

Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study

“…Tü6071, has been previously reported to have antibacterial activity [ 53 ]. Questiomycin A, an analog of actinomycin D, is known to have anticancer properties and cause apoptosis in the different cancer cell lines, but the mechanism of its action is unknown [ 54 ]. We observed in this study that Phenalinolactones A–D and Questiomycin A inhibit the agr -type QS systems and blood hemolysis in S. aureus .…”