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Vol. 61, Issue 4, 720-728, April 2002

Identification of a Potent and Selective Pharmacophore for Cdc25 Dual Specificity Phosphatase Inhibitors.

John S. Lazo, Kaoru Nemoto, Katharine E. Pestell, Kathleen Cooley, Eileen C. Southwick, Douglas A. Mitchell, William Furey, Rick Gussio, Daniel W. Zaharevitz, Beomjun Joo, and Peter Wipf

Departments of Pharmacology (J.S.L., K.N., K.E.P., K.C., E.C.S., D.A.M., W.F.) and Chemistry (B.J., P.W.), University of Pittsburgh, Pittsburgh, Pennsylvania; Veterans Affairs Medical Center, Biocrystallography Laboratory, Pittsburgh, Pennsylvania (W.F.); and Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Rockville, Maryland (R.G., D.W.Z.)

Small molecules provide powerful tools to interrogate biological pathways but many important pathway participants remain refractory to inhibitors. For example, Cdc25 dual-specificity phosphatases regulate mammalian cell cycle progression and are implicated in oncogenesis, but potent and selective inhibitors are lacking for this enzyme class. Thus, we evaluated 10,070 compounds in a publicly available chemical repository of the National Cancer Institute for in vitro inhibitory activity against oncogenic, full-length, recombinant human Cdc25B. Twenty-one compounds had mean inhibitory concentrations of <1 µM; >75% were quinones and >40% were of the para-naphthoquinone structural type. Most notable was NSC 95397 (2,3-bis-[2-hydroxyethylsulfanyl]-[1,4]naphthoquinone), which displayed mixed inhibition kinetics with in vitro Ki values for Cdc25A, -B, and -C of 32, 96, and 40 nM, respectively. NSC 95397 was more potent than any inhibitor of dual specificity phosphatases described previously and 125- to 180-fold more selective for Cdc25A than VH1-related dual-specificity phosphatase or protein tyrosine phosphatase 1b, respectively. Modification of the bis-thioethanol moiety markedly decreased enzyme inhibitory activity, indicating its importance for bioactivity. NSC 95397 showed significant growth inhibition against human and murine carcinoma cells and blocked G2/M phase transition. A potential Cdc25 site of interaction was postulated based on molecular modeling with these quinones. We propose that inhibitors based on this chemical structure could serve as useful tools to probe the biological function of Cdc25.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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