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首页> 外文期刊>Journal of Molecular Biology >Overcoming Drug Resistance through the Development of Selective Inhibitors of UDP-Glucuronosyltransferase Enzymes
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Overcoming Drug Resistance through the Development of Selective Inhibitors of UDP-Glucuronosyltransferase Enzymes

机译：通过开发UDP-葡糖醛糖基三烷基转移酶的选择性抑制剂克服耐药性

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摘要

Drug resistance is a major cause of cancer-related mortality. Glucuronidation of drugs via elevation of UDP-glucuronosyltransferases (UGT1As) correlates with clinical resistance. The nine UGT1A family members have broad substrate specificities attributed to their variable N-terminal domains and share a common C-terminal domain. Development of UGT1As as pharmacological targets has been hampered by toxicity of pan-UGT inhibitors and by difficulty in isolating pure N-terminal domains or full-length proteins. Here, we developed a strategy to target selected UGT1As which exploited the biochemical tractability of the C-domain and its ability to allosterically communicate with the catalytic site. By combining NMR fragment screening with in vitro glucuronidation assays, we identified inhibitors selective for UGT1A4. Significantly, these compounds selectively restored sensitivity in resistant cancer cells only for substrates of the targeted UGT1A. This strategy represents a crucial first step toward developing compounds to overcome unwanted glucuronidation thereby reversing resistance in patients. (C) 2018 Elsevier Ltd. All rights reserved.
机译：耐药性是癌症相关死亡率的主要原因。通过UDP-葡糖醛阳糖基转移酶（UGT1As）升高的药物葡萄糖与临床抗性相关。九个UGT1A系列成员具有​​宽的基质特异性，归因于其变量N末端域并共享公共C终端域。作为药理靶标的泛虫靶标的开发被泛uGT抑制剂的毒性受到阻碍，并且难以分离纯N末端结构域或全长蛋白质。在这里，我们开发了一种靶向所选择的UGT1as的策略，该策略利用C域的生化途径及其与催化部位共同地通信的能力。通过将NMR片段筛选与体外葡糖醛酸化测定组合，我们鉴定了对UGT1A4选择性的抑制剂。值得注意的是，这些化合物仅针对靶向UGT1A的底物选择性地恢复抗性癌细胞的敏感性。该策略代表了发展化合物以克服不希望的葡糖醛化的至关重要步骤，从而逆转患者的抗性。 （c）2018年elestvier有限公司保留所有权利。

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