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.
Highlights
Cell division cycle 25 proteins (CDC25s) are dual-specificity phosphatases (DSPs), acting as key regulators of the cell cycle
CDC25B is responsible for the initial activation of CDK1-Cyclin B complex at the centrosome during the G2/M transition, which is followed by a www.impactjournals.com/oncotarget complete activation of CDK1-Cyclin B complexes by CDC25C in the nucleus at the onset of mitosis [8]
By combining experimental and computational methods, we have identified a set of inhibitors of CDC25 phosphatases, which are key elements in the control of the cell cycle in eukaryote cells, in normal conditions as well as in response to cell damage, and whose overexpression is associated to a wide variety of cancers [8, 21]
Summary
Cell division cycle 25 proteins (CDC25s) are dual-specificity phosphatases (DSPs), acting as key regulators of the cell cycle. CDC25C is present in each cell cycle phase and regulates the G2/M transition, by targeting CDK1Cyclin B complex [11,12]. In order to assure a controlled progression through each cell cycle phase and maintain the genomic integrity, a tight regulation of CDC25 phosphatases activity is needed, both in unperturbed cell cycle and in response to DNA damage checkpoints. This regulation depends upon post-translational mechanisms such as phosphorylations, sub-cellular relocalization and proteasome-mediated degradation [14], together with p53-dependent transcriptional repression of the three CDC25 phosphatases [15,16]. All these observations indicate that CDC25s are promising targets for the development of anti-cancer drugs
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