Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction
| Autor: | Hong Zhang, Benjamin Schwartz, Michael D. Schaber, Mark A. Seefeld, Jon-Paul Jaworski, Guanglei Cui, Shu-Yun Zhang, Kelly Federowicz, Aidan G. Gilmartin, Faitg Thomas H, Martin Brandt, Jingsong Yang, Mark Richter, Robert B. Kirkpatrick, Dean E. McNulty, Neysa Nevins, Arthur Groy, Elsie Diaz, Rakesh Kumar, Stan F. Martens, Amber D. Jones, Dirk A. Heerding, Peng Xin, Robert H. Sinnamon, Elisabeth A. Minthorn, Michael G. Darcy, Beth Pietrak |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Amino Acid Motifs
Phosphatase Allosteric regulation Administration Oral Aminopyridines Antineoplastic Agents Mice SCID Biology Pyruvate dehydrogenase phosphatase Models Biological Mice chemistry.chemical_compound Allosteric Regulation Catalytic Domain Cell Line Tumor Neoplasms Phosphoprotein Phosphatases Animals Humans Enzyme Inhibitors Molecular Biology Kinase Dipeptides Cell Biology Protein phosphatase 2 Enzyme Activation Protein Phosphatase 2C Disease Models Animal chemistry Biochemistry Cell culture Cancer research Heterografts Phosphorylation Female Drug Screening Assays Antitumor Growth inhibition |
| Zdroj: | Nature Chemical Biology. 10:181-187 |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/nchembio.1427 |
| Popis: | Although therapeutic interventions of signal-transduction cascades with targeted kinase inhibitors are a well-established strategy, drug-discovery efforts to identify targeted phosphatase inhibitors have proven challenging. Herein we report a series of allosteric, small-molecule inhibitors of wild-type p53-induced phosphatase (Wip1), an oncogenic phosphatase common to multiple cancers. Compound binding to Wip1 is dependent on a 'flap' subdomain located near the Wip1 catalytic site that renders Wip1 structurally divergent from other members of the protein phosphatase 2C (PP2C) family and that thereby confers selectivity for Wip1 over other phosphatases. Treatment of tumor cells with the inhibitor GSK2830371 increases phosphorylation of Wip1 substrates and causes growth inhibition in both hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Oral administration of Wip1 inhibitors in mice results in expected pharmacodynamic effects and causes inhibition of lymphoma xenograft growth. To our knowledge, GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|