論文

査読有り
2009年11月

Multidentate Small-Molecule Inhibitors of Vaccinia H1-Related (VHR) Phosphatase Decrease Proliferation of Cervix Cancer Cells

JOURNAL OF MEDICINAL CHEMISTRY
  • Shuangding Wu
  • ,
  • Sofie Vossius
  • ,
  • Souad Rahmouni
  • ,
  • Ana V. Miletic
  • ,
  • Torkel Vang
  • ,
  • Jesus Vazquez-Rodriguez
  • ,
  • Fabio Cerignoli
  • ,
  • Yutaka Arimura
  • ,
  • Scott Williams
  • ,
  • Tikva Hayes
  • ,
  • Michel Moutschen
  • ,
  • Stefan Vasile
  • ,
  • Maurizio Pellecchia
  • ,
  • Tomas Mustelin
  • ,
  • Lutz Tautz

52
21
開始ページ
6716
終了ページ
6723
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1021/jm901016k
出版者・発行元
AMER CHEMICAL SOC

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 V H R 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 hovel 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.

Web of Science ® 被引用回数 : 41

リンク情報
DOI
https://doi.org/10.1021/jm901016k
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/19888758
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000271427900024&DestApp=WOS_CPL

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