title: Discovery of new inhibitors of Cdc25B dual specificity phosphatases by structure-based virtual screening.
abstract: Cell division cycle 25 (Cdc25) proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent attractive drug targets for anticancer therapies. To discover more potent and diverse inhibitors of Cdc25 biological activity, virtual screening was performed by docking 2.1 million compounds into the Cdc25B active site. An initial subset of top-ranked compounds was selected and assayed, and 15 were found to have enzyme inhibition activity at micromolar concentration. Among these, four structurally diverse inhibitors with a different inhibition profile were found to inhibit human MCF-7, PC-3, and K562 cancer cell proliferation and significantly affect the cell cycle progression. A subsequent hierarchical similarity search with the most active reversible Cdc25B inhibitor found led to the identification of an additional set of 19 ligands, three of which were confirmed as Cdc25B inhibitors with IC(50) values of 7.9, 4.2, and 9.9 μM, respectively.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Drug Discovery Laboratory, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. lavecchi@unina.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Carmen
authors.initials: C
authors.lastname: Di Giovanni
authors.forename: Ada
authors.initials: A
authors.lastname: Pesapane
authors.forename: Nunzia
authors.initials: N
authors.lastname: Montuori
authors.forename: Pia
authors.initials: P
authors.lastname: Ragno
authors.forename: Nicola Massimiliano
authors.initials: NM
authors.lastname: Martucci
authors.forename: Mariorosario
authors.initials: M
authors.lastname: Masullo
authors.forename: Emmanuele
authors.initials: E
authors.lastname: De Vendittis
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020687:cdc25 Phosphatases