PMID: 11901209Mar 20, 2002Paper

Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors

Molecular Pharmacology
John S LazoPeter Wipf

Abstract

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 microM; >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 K(i) 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...Continue Reading

References

Dec 1, 1991·Journal of Computer-aided Molecular Design·G E KelloggD J Abraham
Dec 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·J B MillarP Russell
Jul 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·K SadhuP Russell
Oct 1, 1995·The Biochemical Journal·S Wera, B A Hemmings
Sep 15, 1995·Science·K GalaktionovD Beach
Aug 8, 1996·Nature·K GalaktionovD Beach
Nov 1, 1996·Cell·J M DenuJ E Dixon
May 18, 1999·Bioorganic & Medicinal Chemistry Letters·C K RyuC O Lee
Feb 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·P GiannakakouT Fojo
Mar 31, 2000·Progress in Cell Cycle Research·I Nilsson, I Hoffmann
Sep 21, 2000·The Journal of Clinical Investigation·M G CangiM Loda
Jan 4, 2001·European Journal of Cell Biology·S WegenerH C Schaller
Apr 17, 2001·Laboratory Investigation; a Journal of Technical Methods and Pathology·S HernándezE Campo
Jan 10, 2002·Biochemical and Biophysical Research Communications·Takaki HiwasaMasaki Takiguchi

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Citations

Feb 9, 2008·Cancer Metastasis Reviews·Zhong-Xing Jiang, Zhong-Yin Zhang
Jun 2, 2005·Bioorganic & Medicinal Chemistry·Shugeng CaoDavid G I Kingston
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
Jan 28, 2003·Drug Discovery Today·Rob Hooft van HuijsduijnenDominique Swinnen
Jul 14, 2011·Biochemistry·Natalya G DulyaninovaAnne R Bresnick
Apr 25, 2012·Journal of Medicinal Chemistry·Antonio LavecchiaEttore Novellino
Jun 5, 2007·Nature Protocols·Marni Brisson TiernoJohn S Lazo
Dec 4, 2002·Nature Reviews. Drug Discovery·Michael A LyonJohn S Lazo
Mar 10, 2009·The Journal of Biological Chemistry·Rekha G PanchalSina Bavari
Jun 18, 2009·Assay and Drug Development Technologies·Paul A JohnstonJohn S Lazo
Jan 15, 2010·Assay and Drug Development Technologies·Karina M SoaresPaul A Johnston
Jan 19, 2012·Molecular and Cellular Biology·Michael G BergGideon Dreyfuss
Apr 12, 2005·Annual Review of Pharmacology and Toxicology·Alexander P DucruetJohn S Lazo
Aug 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·Isabelle LandrieuGuy Lippens
Apr 7, 2010·Bioorganic & Medicinal Chemistry·Benjamin J MulchinBridget L Stocker
Oct 31, 2014·Organic & Biomolecular Chemistry·Luo YangGuo-Jun Deng
Oct 18, 2002·Journal of Cellular Physiology·Brian I CarrSiddhartha Kar
Oct 11, 2013·Journal of Virology·Olivia PerwitasariRalph A Tripp
May 14, 2005·Antioxidants & Redox Signaling·Johannes Rudolph
Mar 8, 2013·Molecular BioSystems·Ayako TsuchiyaMikiko Sodeoka
Jan 27, 2004·Bioorganic & Medicinal Chemistry Letters·Junguk ParkDehua Pei
Sep 19, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lars-Oliver KlotzClaus Jacob
May 31, 2011·Experimental Cell Research·Leda RaptisJames Turkson
Oct 27, 2009·Experimental Cell Research·Rozanne ArulanandamLeda Raptis
May 5, 2009·Current Opinion in Chemical Biology·Viktor V VintonyakHerbert Waldmann
Jul 24, 2012·The FEBS Journal·Rongjun HeZhong-Yin Zhang
Jan 18, 2005·Biochemical and Biophysical Research Communications·Ira MelchheierLars-Oliver Klotz
Jan 7, 2015·Cell Cycle·Yann ThomasVéronique Baldin
Feb 21, 2006·Current Opinion in Cell Biology·Rose BoutrosBernard Ducommun
Jan 29, 2014·Biochemical Pharmacology·Yanyan YangJae Youl Cho
Dec 11, 2002·Expert Opinion on Therapeutic Targets·Rob Hooft van HuijsduijnenAxel Harrenga
Jan 31, 2006·Expert Opinion on Therapeutic Targets·Lutz TautzTomas Mustelin
Jan 29, 2014·JAK-STAT·Mulu GeletuLeda Raptis
Apr 2, 2013·Biochimica Et Biophysica Acta·M GeletuL Raptis

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