Bisubstrate inhibitors to target histone acetyltransferase 1

机译：将靶向组蛋白乙酰转移酶1的体育抑制剂1

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Abstract > Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 ( <fc>HAT</fc> 1) is among the first histone acetyltransferase ( <fc>HAT</fc> ) enzymes that were discovered in the mid‐1990s; however, it remains one of the poorly studied enzymes in comparison with the other <fc>HAT</fc> s. Although <fc>HAT</fc> 1 has been linked to various disease states, no inhibitors have been reported to target <fc>HAT</fc> 1. Here, we designed a set of peptide‐CoA conjugates as bisubstrate inhibitors of <fc>HAT</fc> 1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a low K <sub>i</sub> value of 1.1?nM for <fc>HAT</fc> 1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism of <fc>HAT</fc> 1 catalysis. Creating these submicromolar inhibitors offers mechanistic tools to better understand how <fc>HAT</fc> 1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“main”XML：ID =“CBDD13476-ABS-ABS-0001”XML：Lang =“EN”> <标题类型=“main”>摘要</标题> >开发选择性酶抑制剂允许扩展分子工具箱研究靶酶的功能和活性。组蛋白乙酰转移酶1（<Fc>帽子</ Fc> 1）是在20世纪90年代中期发现的第一组蛋白乙酰转移酶（<Fc>帽子/ Fc>）中;然而，与其他<FC>帽子相比，它仍然是较差的酶之一。虽然<Fc>帽子</ fc> 1已链接到各种疾病状态，但没有据报道靶向<Fc>帽子</ Fc> 1.在这里，我们设计了一组肽-CoA缀合物，为Bisubss抑制剂<Fc>帽子</ Fc> 1，具有亚微粒溶胶效力。特别地，Bisubstrate抑制剂H4K12COA表现出低的<I> K / ke> I </ sub>值为1.1Ω·nm for <fc>帽子</ fc> 1.此外，显示H4K12COA竞争性抑制剂关于AccoA和H4肽，表明<Fc>帽的独特动力学机制</ Fc> 1催化。创建这些潜在的潜在含量抑制剂提供机械工具，以更好地了解<FC>帽子如何识别底物和辅助剂，以及提供化学物质，以进一步开发治疗剂以靶向疾病治疗的这一重要酶。 </ p> </ abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-16096/'>《Chemical biology and drug design》</a> <b style="margin: 0 2px;">|</b><span>2019年第5期</span><b style="margin: 0 2px;">|</b><span>共9页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Ngo Liza&option=202" target="_blank" rel="nofollow">Ngo Liza;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Brown Tyler&option=202" target="_blank" rel="nofollow">Brown Tyler;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Zheng Yujun G.&option=202" target="_blank" rel="nofollow">Zheng Yujun G.;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of Pharmaceutical and Biomedical SciencesUniversity of GeorgiaAthens Georgia;</p> <p>Department of Pharmaceutical and Biomedical SciencesUniversity of GeorgiaAthens Georgia;</p> <p>Department of Pharmaceutical and Biomedical SciencesUniversity of GeorgiaAthens Georgia;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/6411.html" title="化学药理学">化学药理学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=bisubstrate inhibitor&option=203" rel="nofollow">bisubstrate inhibitor;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=chemical probes&option=203" rel="nofollow">chemical probes;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=epigenetics&option=203" rel="nofollow">epigenetics;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=HAT&option=203" rel="nofollow">HAT;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=HAT 1&option=203" rel="nofollow">HAT 1;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=histone acetyltransferase&option=203" rel="nofollow">histone acetyltransferase;</a> </p> <div class="translation"> 机译：Bisubstate抑制剂;化学探针;表观遗传学;帽子;帽子1;组蛋白乙酰转移酶; 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A.,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Kumar, A.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Kumar, A.,</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Dhar, S.&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">Dhar, S.,</a> <span>2017</span> </span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：通过紫檀芪与组蛋白去乙酰化酶抑制剂组合靶向mTa1 / HIF-1α信号减弱前列腺癌进展（开放存取）。</span> </p> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/academic-journal-cn_journal-modern-oncology_thesis/0201236492491.html">DNA甲基化转移酶抑制剂和组蛋白脱乙酰化酶抑制剂的体外抗肿瘤作用</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=彭恩兰&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 彭恩兰</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=陈卫民&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,陈卫民</a> <span> <a href="/journal-cn-6207/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 现代肿瘤医学 </a> </span> <span> . 2008</span><span>,第001期</span> </span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/academic-journal-cn_journal-modern-oncology_thesis/0201236440198.html">组蛋白去乙酰化转移酶抑制剂MS-275对胃癌细胞增殖的影响</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=任亚婵&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 任亚婵</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=刘瑾&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,刘瑾</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=吴智群&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,吴智群</a> <span> <a href="/journal-cn-6207/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 现代肿瘤医学 </a> </span> <span> . 2012</span><span>,第005期</span> </span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/academic-journal-cn_journal-heilongjiang-bayi-agricultural-university_thesis/02012279953.html">5-aza-2'脱氧胞啶联合组蛋白乙酰基转移酶抑制剂LAQ对体外RD-ES细胞的抑制作用</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=刘哲&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 刘哲</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=张峰&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,张峰</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=佟丹丹&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,佟丹丹</a> <span> <a href="/journal-cn-7235/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 黑龙江八一农垦大学学报 </a> </span> <span> . 2010</span><span>,第001期</span> </span> </div> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/academic-journal-cn_detail_thesis/0201293956254.html">去甲基化和组蛋白去乙酰化转移酶抑制剂对Ishikawa和AN3细胞增殖和凋亡的影响</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=尚建强&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 尚建强</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=贾婷&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,贾婷</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=陈方方&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,陈方方</a> <span> <a href="/journal-cn-56969/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 中华肿瘤防治杂志 </a> </span> <span> . 2007</span><span>,第9期</span> </span> </div> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/academic-journal-cn_detail_thesis/0201294576617.html">新型靶向组蛋白去乙酰化酶抑制剂的抗肿瘤作用及其机制</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=金惠&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 金惠</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=刘力锋&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,刘力锋</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=邓卫平&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,邓卫平</a> <span> <a href="/journal-cn-57041/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 中国药科大学学报 </a> </span> <span> . 2013</span><span>,第4期</span> </span> </div> </li> <li> <div> <b>6. </b><a class="enjiyixqcontent" href="/academic-conference-cn_meeting-443_thesis/02022935931.html">菜薹组蛋白乙酰转移酶基因BrcuHAC1的克隆和表达分析</a> <b>[C]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=XIAO Xu-feng&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 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href="/patent-detail/06120103363526.html">组蛋白乙酰转移酶P300小分子抑制剂及其药用组合物及其应用</a> <b>[P]</b> . <span> 中国专利： CN110862383A </span> <span> . 2020-03-06</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/06120104119240.html">MYST家族组蛋白乙酰转移酶抑制剂</a> <b>[P]</b> . <span> 中国专利： CN111565717A </span> <span> . 2020-08-21</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130437776202.html">Methods and compositions of bisubstrate inhibitors of acetyltransferases</a> <b>[P]</b> . <span> 外国专利：  DK1212056T3 </span> <span> . 2006-04-03</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：乙酰转移酶双底物抑制剂的方法和组成 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130437402686.html">METHODS AND COMPOSITIONS FOR BISUBSTRATE INHIBITORS OF ACETYLTRANSFERASES</a> <b>[P]</b> . <span> 外国专利：  EP1212056B1 </span> <span> . 2005-12-07</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：乙酰转移酶双底物抑制剂的方法和组成 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130439785356.html">Methods and compositions for bisubstrate inhibitors of acetyltransferases</a> <b>[P]</b> . <span> 外国专利：  AU780891B2 </span> <span> . 2005-04-21</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：乙酰转移酶双底物抑制剂的方法和组合物 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> <ul id="subject"> </ul> </div> </div> </div> </div> <div class="right rightcon"> <div class="details_img cardcommon clearfix" 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