Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
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痘苗 H1 相关 (VHR) 磷酸酶的多齿小分子抑制剂可减少宫颈癌细胞的增殖。
DOI：
10.1021/jm901016k
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发表时间：
2009
影响因子：
7.3
通讯作者：
Tautz,Lut
中科院分区：
文献类型：
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作者：
Wu,Shuangding;Vossius,Sofie;Rahmouni,Souad;Miletic,AnaV;Vang,Torkel;Vazquez-Rodriguez,Jesus;Cerignoli,Fabio;Arimura,Yutaka;Williams,Scott;Hayes,Tikva;Moutschen,Michel;Vasile,Stefan;Pellecchia,Maurizio;Mustelin,Tomas;Tautz,Lut
VHR磷酸酶的缺失导致HeLa癌细胞周期停滞，提示抑制VHR可能是阻止癌细胞生长的有效途径。我们最近报道了VHR在几个宫颈癌细胞系以及子宫颈癌中表达上调。在这里，我们报道了VHR的多齿小分子抑制剂的发展，这些抑制剂在纳摩尔浓度下抑制VHR的酶活性，并显示出对宫颈癌细胞的抗增殖作用。使用化学库筛选来鉴定命中化合物，这些化合物在轮廓分析和动力学实验中进一步优先考虑。应用SAR分析寻找具有更高效力和选择性的类似物，结果发现了能够与VHR活性部位内的磷酸盐结合口袋和几个不同的疏水区域相互作用的新型抑制剂。X-射线结晶学证实了这种多齿结合模式。这些抑制剂抑制宫颈癌细胞的增殖，而对原代正常角质形成细胞的生长没有影响。这些化合物可能是开发治疗宫颈癌药物的起点。
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.