Article (Scientific journals)
Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
Wu, Shuangding; Vossius, Sofie; Rahmouni, Souad et al.
2009In Journal of Medicinal Chemistry, 52 (21), p. 6716-23
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Keywords :
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
Abstract :
[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.
Research center :
GIGA-I3 - Giga-Infection, Immunity and Inflammation - ULiège
Disciplines :
Immunology & infectious disease
Biochemistry, biophysics & molecular biology
Author, co-author :
Wu, Shuangding ;  Burnham Institute for Medical Research (La Jolla, California) > Infectious and Inflammatory Disease Center and Cancer Center
Vossius, Sofie  ;  Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén.
Rahmouni, Souad   ;  Université de Liège - ULiège > 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  ;  Université de Liège - ULiège > 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
More authors (5 more) Less
 These authors have contributed equally to this work.
Language :
English
Title :
Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
Publication date :
12 November 2009
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
52
Issue :
21
Pages :
6716-23
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 22 November 2010

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