title: Ligand-based chemoinformatic discovery of a novel small molecule inhibitor targeting CDC25 dual specificity phosphatases and displaying in vitro efficacy against melanoma cells.
abstract: CDC25 phosphatases are important regulators of the cell cycle and represent promising targets for anticancer drug discovery. We recently identified NSC 119915 as a new quinonoid CDC25 inhibitor with potent anticancer activity. In order to discover more active analogs of NSC 119915, we performed a range of ligand-based chemoinformatic methods against the full ZINC drug-like subset and the NCI lead-like set. Nine compounds (3, 5-9, 21, 24, and 25) were identified with Ki values for CDC25A, -B and -C ranging from 0.01 to 4.4 μM. One of these analogs, 7, showed a high antiproliferative effect on human melanoma cell lines, A2058 and SAN. Compound 7 arrested melanoma cells in G2/M, causing a reduction of the protein levels of CDC25A and, more consistently, of CDC25C. Furthermore, an intrinsic apoptotic pathway was induced, which was mediated by ROS, because it was reverted in the presence of antioxidant N-acetyl-cysteine (NAC). Finally, 7 decreased the protein levels of phosphorylated Akt and increased those of p53, thus contributing to the regulation of chemosensitivity through the control of downstream Akt pathways in melanoma cells. Taken together, our data emphasize that CDC25 could be considered as a possible oncotarget in melanoma cells and that compound 7 is a small molecule CDC25 inhibitor that merits to be further evaluated as a chemotherapeutic agent for melanoma, likely in combination with other therapeutic compounds.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Capasso
authors.affiliation: Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cerchia
authors.affiliation: Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Di Giovanni
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Granato
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Albano
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Romano
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: De Vendittis
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ruocco
authors.affiliation: Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D054637:Dual-Specificity Phosphatases; D020687:cdc25 Phosphatases
keywords: CDC25 phosphatases; cancer; cell cycle; drug discovery; melanoma cells