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[Cancer Research 64, 3320-3325, May 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

A Novel Synthetic Inhibitor of CDC25 Phosphatases

BN82002

Marie-Christine Brezak1, Muriel Quaranta2, Odile Mondésert2, Marie-Odile Galcera1, Olivier Lavergne1, Frédéric Alby2, Martine Cazales2, Véronique Baldin2, Christophe Thurieau1, Jeremiath Harnett1, Christophe Lanco1, Philip G. Kasprzyk1,3, Gregoire P. Prevost1 and Bernard Ducommun2

1 IPSEN, Institut Henri Beaufour, Les Ulis Cedex, France; 2 Laboratoire de Biologie Cellulaire et Moleculaire du Controle de la Proliferation-Centre National de la Recherche Scientifique UMR5088-IFR109 "Institut d’Exploration Fonctionnelle des Génomes," Université Paul Sabatier, Toulouse, France; and 3 IPSEN, Biomeasure, Milford, Massachusetts

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.




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