Oncotarget

Research Papers:

Ligand-based chemoinformatic discovery of a novel small molecule inhibitor targeting CDC25 dual specificity phosphatases and displaying in vitro efficacy against melanoma cells

Alessandra Capasso _, Carmen Cerchia, Carmen Di Giovanni, Giuseppina Granato, Francesco Albano, Simona Romano, Emmanuele De Vendittis, Maria Rosaria Ruocco and Antonio Lavecchia

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:40202-40222. https://doi.org/10.18632/oncotarget.5473

Metrics: PDF 845 views  |   HTML 1077 views  |   ?  


Abstract

Alessandra Capasso1,*, Carmen Cerchia2,*, Carmen Di Giovanni2, Giuseppina Granato1, Francesco Albano1, Simona Romano1, Emmanuele De Vendittis1, Maria Rosaria Ruocco1, Antonio Lavecchia2

1Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy

2Department of Pharmacy, “Drug Discovery” Laboratory, University of Naples Federico II, 80131 Naples, Italy

*These authors have contributed equally to this work

Correspondence to:

Maria Rosaria Ruocco, e-mail: mariarosaria.ruocco2@unina.it

Antonio Lavecchia, e-mail: antonio.lavecchia@unina.it

Keywords: cancer, CDC25 phosphatases, drug discovery, cell cycle, melanoma cells

Received: April 26, 2015     Accepted: October 02, 2015     Published: October 13, 2015

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 5473