Journal ArticleDOI
Identification of a Potent and Selective Pharmacophore for Cdc25 Dual Specificity Phosphatase Inhibitors.
John S. Lazo,Kaoru Nemoto,Katharine Pestell,Kathleen A Cooley,Eileen C. Southwick,Douglas A. Mitchell,William Furey,Rick Gussio,Daniel W. Zaharevitz,Beomjun Joo,Peter Wipf +10 more
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TLDR
It is proposed that inhibitors based on this chemical structure could serve as useful tools to probe the biological function of Cdc25 and modification of the bis-thioethanol moiety markedly decreased enzyme inhibitory activity, indicating its importance for bioactivity.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 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 its importance for bioactivity. NSC 95397 showed significant growth inhibition against human and murine carcinoma cells and blocked G(2)/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.read more
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The when and wheres of CDC25 phosphatases.
TL;DR: Recent data demonstrate that in addition to the ATM/ATR-CHK pathway, a p38-MAPKAP pathway is also involved in controlling CDC25 activity during G(2)/M checkpoint activation and highlight the significance of developing specific CDC25 inhibitors for cancer therapy.
Journal ArticleDOI
Inhibitors of Protein Tyrosine Phosphatases: Next-Generation Drugs?
Laurent Bialy,Herbert Waldmann +1 more
TL;DR: In this review, general aspects of PTPs and the development of small-molecule inhibitors of PTCs by both academic research groups and pharmaceutical companies are discussed and constitute the basis for the future development of P TP inhibitors as drugs.
Journal ArticleDOI
Discovery of a novel shp2 protein tyrosine phosphatase inhibitor.
Liwei Chen,Shen Shu Sung,M.L. Richard Yip,Harshani R. Lawrence,Yuan Ren,Wayne C. Guida,Said M. Sebti,Nicholas J. Lawrence,Jie Wu +8 more
TL;DR: NSC-87877 is identified as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect and provides the first pharmacological evidence that Shp 2 mediates EGF-induced Erk1/2 MAP kinase activation.
Journal ArticleDOI
1,4-naphthoquinones: from oxidative damage to cellular and inter-cellular signaling.
TL;DR: Generation of reactive oxygen species and modulation of redox signaling are properties of naphthoquinones that render them interesting leads for the development of novel compounds of potential use in various therapeutic settings.
Journal ArticleDOI
Selecting protein tyrosine phosphatases as drug targets.
TL;DR: The history of PTP1B shows that its unusual knockout phenotype and observations with generic and antisense inhibitors in vivo, but not its classical molecular biology, triggered the rapid development of inhibitors that are today being developed for the clinic.
References
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Journal ArticleDOI
Rapid destruction of human Cdc25A in response to DNA damage.
Niels Mailand,Jacob Falck,Claudia Lukas,Randi G. Syljuåsen,Markus Welcker,Jiri Bartek,Jiri Lukas +6 more
TL;DR: These results identify specific degradation of Cdc25A as part of the DNA damage checkpoint mechanism and suggest how CDC25A overexpression in human cancers might contribute to tumorigenesis.
Journal ArticleDOI
Ribbons 2.0
TL;DR: RIBBONS 2.0 as mentioned in this paper allows real-time viewing of solid shaded ribbon models of macromolecules, including spheres, cylinders, dots, polygons and text.
Journal ArticleDOI
Cdc25 cell-cycle phosphatase as a target of c- myc
TL;DR: Findings indicate that cdc25A is a physiologically relevant transcriptional target of c-myc, a proto-oncogene that can promote either oncogenic transformation or apoptosis in cells depleted of growth factor.
Journal ArticleDOI
Serine/threonine protein phosphatases
S Wera,Brian A. Hemmings +1 more
TL;DR: Type-1 phosphatases are insensitive to the heat-stable inhibitors and preferentially dephosphorylate the x-subunit of phosphorylase kinase, whereas type-2 phosphatase can be further subdivided into spontaneously active (PP2A), Ca2l-dependent (PP 2B) and Mg2+dependent ( PP2C) classes.
Journal ArticleDOI
CDC25 Phosphatases as Potential Human Oncogenes
Konstantin Galaktionov,Arthur K.C. Lee,Jens Eckstein,Giulio Draetta,Jason Meckler,Massimo Loda,David Beach +6 more
TL;DR: In rodent cells, human CDC25A or CDC25B but not CDC25C phosphatases cooperate with either Ha-RASG12V or loss of RB1 in oncogenic focus formation, and transformants were highly aneuploid, grew in soft agar, and formed high-grade tumors in nude mice.