Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase

Molecular Pharmacology
Marni BrissonJohn S Lazo

Abstract

Cdc25A and Cdc25B dual-specificity phosphatases are key regulators of cell cycle transition and proliferation. They have oncogenic properties and are overexpressed in many human tumors. Because selective Cdc25 phosphatase inhibitors would be valuable biological tools and possible therapeutic agents, we have assayed a small molecule library for in vitro inhibition of Cdc25. We now report the identification of two new structurally distinct classes of Cdc25 inhibitors with cellular activity. The cyclopentaquinoline 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4,8-dicarboxylic acid (5661118) and the naphthofurandione 3-benzoyl-naphtho[1,2-b]furan-4,5-dione (5169131) had in vitro IC50 values of 2.5 to 11 microM against recombinant Cdc25 and were less potent inhibitors of other phosphatases. Unlike 5661118, 5169131 caused reversible inhibition of Cdc25B and displayed competitive inhibitor kinetics. No growth inhibitory activity was seen with 5661118, whereas 10 to 30 microM 5169131 caused G1/S and G2/M arrest. We also found that 5169131 inhibited human PC-3 prostate and MDA-MB-435 breast cancer cell proliferation. Concentration-dependent Tyr15 hyperphosphorylation was seen on cyclin-dependent kinase with a 1-h 5169131 treatment, co...Continue Reading

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Citations

Jun 1, 2005·Bioorganic & Medicinal Chemistry·Marie-Priscille BrunChristiane Garbay
Apr 21, 2005·Seminars in Cell & Developmental Biology·Julie P I Welburn, Jane A Endicott
Apr 25, 2012·Journal of Medicinal Chemistry·Antonio LavecchiaEttore Novellino
Jun 5, 2007·Nature Protocols·Marni Brisson TiernoJohn S Lazo
Jun 15, 2007·Nature Reviews. Cancer·Rose BoutrosBernard Ducommun
Jun 18, 2009·Assay and Drug Development Technologies·Paul A JohnstonJohn S Lazo
Sep 27, 2008·Acta Pharmacologica Sinica·Xu FengJia Li
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