title: A novel synthetic inhibitor of CDC25 phosphatases: BN82002.
abstract: CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models. BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro. It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G1-S, in S phase and at the G2-M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G1 phase. Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice. BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target.
authors.affiliation: IPSEN, Institut Henri Beaufour, Les Ulis, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Brezak
authors.forename: Muriel
authors.initials: M
authors.lastname: Quaranta
authors.forename: Odile
authors.initials: O
authors.lastname: Mondésert
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Galcera
authors.forename: Olivier
authors.initials: O
authors.lastname: Lavergne
authors.forename: Frédéric
authors.initials: F
authors.lastname: Alby
authors.forename: Martine
authors.initials: M
authors.lastname: Cazales
authors.forename: Véronique
authors.initials: V
authors.lastname: Baldin
authors.forename: Christophe
authors.initials: C
authors.lastname: Thurieau
authors.forename: Jeremiath
authors.initials: J
authors.lastname: Harnett
authors.forename: Christophe
authors.initials: C
authors.lastname: Lanco
authors.forename: Philip G
authors.initials: PG
authors.lastname: Kasprzyk
authors.forename: Gregoire P
authors.initials: GP
authors.lastname: Prevost
authors.forename: Bernard
authors.initials: B
authors.lastname: Ducommun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005021:Ethylamines; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D009574:Nitro Compounds; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C487203:BN82002; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005021:Ethylamines; D009574:Nitro Compounds; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases