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.