Reference : Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decre...
[en] Scientific journals : Article
Human health sciences : Immunology & infectious disease
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/33879
[en] Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
English
Wu, Shuangding [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Vossius, Sofie mailto [Université de Liège - ULg > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén. >]
Rahmouni, Souad mailto [Université de Liège - ULg > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén. >]
Miletic, Ana V. [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Vang, Torkel [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Vazquez-Rodriguez, Jesus [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Cerignoli, Fabio [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Arimura, Yutaka [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Williams, Scott [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Hayes, Tikva [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Moutschen, Michel mailto [Université de Liège - ULg > > Maladies infectieuses et médecine interne générale >]
Vasile, Stefan [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Pellecchia, Maurizio [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Mustelin, Tomas [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
Tautz, Lutz [Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center >]
12-Nov-2009
Journal of Medicinal Chemistry
American Chemical Society
52
21
6716-23
Yes (verified by ORBi)
International
0022-2623
1520-4804
Washington
DC
[en] phosphatases ; cancer ; human papillomavirus ; Multidentate Small-Molecule ; Cell Line, Tumor ; Crystallography, X-Ray ; Databases, Factual ; Drug Screening Assays, Antitumor ; Dual Specificity Phosphatase 3/antagonists & inhibitors/chemistry ; Female ; Humans ; Keratinocytes/drug effects ; Kinetics ; Models, Molecular ; Protein Binding ; Stereoisomerism ; Structure-Activity Relationship ; Sulfonic Acids ; Thiazolidines/chemical synthesis/chemistry/isolation & purification ; Uterine Cervical Neoplasms ; VHR inhibitors
[en] Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR’s active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer.
Giga-Infection, Immunity and Inflammation
Researchers ; Professionals ; Students ; General public
http://hdl.handle.net/2268/33879
also: http://hdl.handle.net/2268/73694
10.1021/jm901016k

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