Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer

He Shipeng; Dong Guoqiang; Li Yu; Wu Shanchao; Wang Wei; Sheng Chunquan

摘要

Abstract > As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small‐molecule inhibitors that simultaneously target bromodomain and extra‐terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor ( 13?a ) is identified to possess excellent and balanced activities against BRD4 BD1 (IC <sub>50</sub> =11?n <sc>m</sc> ) and HDAC1 (IC <sub>50</sub> =21?n <sc>m</sc> ). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)‐JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer. </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：Lang =“en”> <标题类型=“main”>抽象</ title> > 作为预后极差和致命的人类恶性肿瘤之一，迫切需要更有效的治疗胰腺癌。这里报道的是一种新的，有效的治疗策略和小分子抑制剂的设计，其同时靶向溴琼酱和外末端（BET）和组蛋白脱乙酰酶（HDAC），可能是胰腺癌的有前途的治疗剂。一个高度有效的双重抑制剂（ 13？a </ b> ）被确定为对BRD4 BD1（IC）的优异和平衡活动 <sub> 50 </ sub> = 11？n <sc> m </ sc> ）和HDAC1（IC <sub> 50 </ sub> = 21？n <sc> m </ sc> ）。值得注意的是，该化合物在体外和体内抗肿瘤效力方面表现出比BET抑制剂（+） - JQ1和HDAC抑制剂Vorinostat，突出突出/ HDAC双抑制剂的优点，以便更有效地治疗胰腺癌症。 </ p> </摘要> </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-19011/'>《Angewandte Chemie》</a> <b style="margin: 0 2px;">|</b><span>2020年第8期</span><b style="margin: 0 2px;">|</b><span>共5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=He Shipeng&option=202" target="_blank" rel="nofollow">He Shipeng;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Dong Guoqiang&option=202" target="_blank" rel="nofollow">Dong Guoqiang;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Li Yu&option=202" target="_blank" rel="nofollow">Li Yu;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wu Shanchao&option=202" target="_blank" rel="nofollow">Wu Shanchao;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wang Wei&option=202" target="_blank" rel="nofollow">Wang Wei;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Sheng Chunquan&option=202" target="_blank" rel="nofollow">Sheng Chunquan;</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>School of PharmacySecond Military Medical University325 Guohe Road Shanghai 200433 China;</p> <p>School of PharmacySecond Military Medical University325 Guohe Road Shanghai 200433 China;</p> <p>School of PharmacySecond Military Medical University325 Guohe Road Shanghai 200433 China;</p> <p>School of PharmacySecond Military Medical University325 Guohe Road Shanghai 200433 China;</p> <p>School of PharmacyEast China University of Science and Technology130 Meilong Road Shanghai 200237 China;</p> <p>School of PharmacySecond Military Medical University325 Guohe Road Shanghai 200433 China;</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/1188.html" title="应用化学">应用化学;</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=anticancer&option=203" rel="nofollow">anticancer;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=antitumor agents&option=203" rel="nofollow">antitumor agents;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=drug discovery&option=203" rel="nofollow">drug discovery;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=heterocyles&option=203" rel="nofollow">heterocyles;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=inhibitors&option=203" rel="nofollow">inhibitors;</a> </p> <div class="translation"> 机译：抗癌;抗肿瘤剂;药物发现;杂交;抑制剂; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" 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href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=ZHANG Ying-jie&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . ZHANG Ying-jie</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=张颖杰&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,张颖杰</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=LI Xiao-yang&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,LI Xiao-yang</a> <span> <a href="/conference-cn-2560/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 第十二届全国青年药学工作者最新科研成果交流会 </a> <span> <span> . 2014</span> </span> </div> </li> <li> <div> <b>7. </b><a class="enjiyixqcontent" href="/academic-degree-domestic_mphd_thesis/020316320338.html">吲哚类HDAC6/Tubulin双靶点抑制剂的筛选及其抗白血病作用研究</a> <b>[A] </b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=乔兴慧&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 乔兴慧</a> <span> . 2021</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/06120112052635.html">用于癌症治疗的包含HDAC抑制剂、LAG-3抑制剂和PD-1抑制剂或PD-L1抑制剂的组合</a> <b>[P]</b> . <span> 中国专利： CN112055589A </span> <span> . 2020-12-08</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/061201448246.html">使用组蛋白脱乙酰基酶HDAC1、HDAC2和/或HDAC3的选择性抑制剂和微管稳定剂的癌症组合治疗</a> <b>[P]</b> . <span> 中国专利： CN101861151B </span> <span> . 2014.08.13</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130406771081.html">Method to determine if an individual is affected by a cancer, Method to discriminate between colorectal and pancreatic cancer among individuals who turn out to be positive for the method, Method to determine the stage of a colorectal cancer in an affected individual, and Use of an rt kit -pcr quantitative to perform the method</a> <b>[P]</b> . <span> 外国专利：  BR112016013976A2 </span> <span> . 2018-01-09</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：确定一个人是否受癌症影响的方法，在对该方法呈阳性的个体中区分结肠直肠癌和胰腺癌的方法，确定一个患病个体中结肠直肠癌的分期的方法以及rt kit -pcr定量执行方法 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130437795445.html">Carbonyl compounds as inhibitors of histona deacetilase for treatment of diseases; the pharmaceutical composition; method of modulating the activity of HDAC catalu00ectica; method of treating disease in an individualu00ecduo; use of a compound or composition, method of inhibiting HDAC</a> <b>[P]</b> . <span> 外国专利：  BRPI0411275A </span> <span> . 2006-08-01</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：羰基化合物作为组蛋白去乙酰化酶抑制剂，用于治疗疾病;药物组合物;调节HDAC催化活性的方法治疗个体疾病的方法化合物或组合物的用途，抑制HDAC的方法 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130406770980.html">methods for identifying a cancer stem cell zone, an adenoma-adenocarcinoma transition zone, a colon tumor, cancer stem cells, an individual with colorectal cancer likely to respond favorably to treatment with an nf-targeted therapy -kb, an individual with genomic loss of 18q / smad4 and 10q / pten, to diagnose an individual with a high degree of colon adenoma and early adenocarcinoma, and to determine the likelihood of a colon tumor in an individual undergoing a transformation. invasive if left untreated and the likelihood that an individual with colorectal cancer (CRC) will respond favorably to treatment with targeted tgf-beta therapy, and a kit to identify an adenoma-adenocarcinoma transition region in a tumor sample from colon</a> <b>[P]</b> . <span> 外国专利：  BR112016017132A2 </span> <span> . 2018-01-30</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：鉴定癌症干细胞区，腺瘤-腺癌过渡区，结肠肿瘤，癌症干细胞，可能对nf靶向疗法-kb进行治疗的结直肠癌患者，基因组丢失的个体的方法18q / smad4和10q / pten用于诊断患有高度结肠腺瘤和早期腺癌的个体，并确定个体发生结肠癌的可能性。如果不进行治疗，将具有侵袭性，并且结肠直肠癌（CRC）患者将对靶向tgf-β治疗产生良好反应的可能性，以及从结肠癌样本中鉴定出腺瘤-腺癌过渡区域的试剂盒 </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" style="margin-bottom: 10px;display:none;" > </div> </div> </div> <div id="thesis_get_original1" class="downloadBth" style="bottom: 19px;z-index: 999;" onclick="ywcd('0704028161573','4',7,2,1,'',this,24)" class="delivery" prompt="010401" title="通过人工服务将文献原文发送至邮箱" >获取原文</div> <div class="journalsub-pop-up" style="display: none"> <div class="journal-sub"> <h2>期刊订阅</h2> <img src="https://cdn.zhangqiaokeyan.com/img/loginclose.png" alt="关闭" 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