• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>PLoS Clinical Trials >Discovery of novel multidrug resistance protein 4 (MRP4) inhibitors as active agents reducing resistance to anticancer drug 6-Mercaptopurine (6-MP) by structure and ligand-based virtual screening
【2h】

Discovery of novel multidrug resistance protein 4 (MRP4) inhibitors as active agents reducing resistance to anticancer drug 6-Mercaptopurine (6-MP) by structure and ligand-based virtual screening

机译：通过基于结构和配体的虚拟筛选发现了新型多药耐药蛋白4（MRP4）抑制剂作为活性剂，可降低对抗癌药6-巯基嘌呤（6-MP）的耐药性

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Multidrug resistance protein 4 (MRP4/ABCC4) is an ATP-binding cassette (ABC) transporter. It is associated with multidrug resistance (MDR), which is becoming a growing challenge to the treatment of cancer and infections. In the context of several types of cancer in which MRP4 is overexpressed, MRP4 inhibition manifests striking effects against cancer progression and drug resistance. In this study, we combined ligand-based and structure-based drug design strategy, by searching the SPECS chemical library to find compounds that are most likely to bind to MRP4. Clustering analysis based on a two-dimensional fingerprint was performed to help with visual selection of potential compounds. Cell viability assays with potential inhibitors and the anticancer drug 6-MP were carried out to identify their bioactivity. As a result, 39 compounds were tested and seven of them reached inhibition above 55% with 6-MP. Then compound Cpd23 was discovered to improve HEK293/MRP4 cell sensibility to 6-MP dramatically, and low concentration Cpd23 (5 μM) achieved the equivalent effect of 50 μM MK571. The accumulation of 6-MP was determined by validated high-performance liquid chromatography methods, and pretreatment of the HEK293/MRP4 cells with 50 μM MK571 or Cpd23 resulted in significantly increased accumulation of 6-MP by approximately 1.5 times. This compound was first reported with a novel scaffold compared with previously known MRP4 inhibitors, which is a hopeful molecular tool that can be used for overcoming multidrug resistance research.
机译：多重耐药蛋白4（MRP4 / ABCC4）是ATP结合盒（ABC）转运蛋白。它与多药耐药性（MDR）相关，这对癌症和感染的治疗正成为日益严峻的挑战。在MRP4过表达的几种类型的癌症的背景下，MRP4抑制作用表现出显着的抗癌进程和耐药性的作用。在这项研究中，我们通过搜索SPECS化学文库以查找最有可能与MRP4结合的化合物，将基于配体和基于结构的药物设计策略相结合。进行了基于二维指纹的聚类分析，以帮助视觉选择潜在的化合物。用潜在的抑制剂和抗癌药6-MP进行细胞活力测定以鉴定其生物活性。结果，测试了39种化合物，其中7种化合物被6-MP抑制超过55％。然后发现化合物 Cpd23 可以显着提高HEK293 / MRP4细胞的敏感性至6-MP，低浓度的 Cpd23 （5μM）达到了50μMMK571的等效作用。通过有效的高效液相色谱法确定6-MP的积累，并用50μMMK571或 Cpd23 预处理HEK293 / MRP4细胞，导致6-MP的积累显着增加约1.5次。与以前已知的MRP4抑制剂相比，该化合物首次被报道使用新型支架，这是一种有希望的分子工具，可用于克服多药耐药性研究。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号