Targeting the Small GTPase Superfamily through Their Regulatory Proteins

Gray Janine L.; Delft Frank; Brennan Paul E.

摘要

Abstract >The Ras superfamily of small GTPases are guanine‐nucleotide‐dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as “undruggable”. The GTP‐dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re‐evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell‐based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins. </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> >小GTP酶的RAS超家族是对许多细胞过程必不可少的鸟嘌呤 - 核苷酸依赖性开关。这些蛋白质的突变或失呼与许多疾病有关，但直接靶向小GTP酶的尝试不成功地导致他们被归类为“不可挽回”。这些蛋白质的GTP依赖性信号由其调节器控制;鸟嘌呤核苷酸交换因子（GEF），GTP酶活性蛋白质（间隙），以及在rho和Rab亚壳中，鸟嘌呤核苷酸解离抑制剂（GDIS）。本综述涵盖了最近通过其监管机构瞄准小型GTP酶的小分子和生物学策略。它旨在重新评估最近的化学生物学实践，例如使用弱效率或未知特异性的化合物的疼痛主题和基于细胞的读出。它突出了通过其调节蛋白将来瞄准小GTP酶的潜在方法的巨大范围。</ 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16期</span><b style="margin: 0 2px;">|</b><span>共25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=Gray Janine L.&option=202" target="_blank" rel="nofollow">Gray Janine L.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Delft Frank&option=202" target="_blank" rel="nofollow">Delft Frank;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Brennan Paul E.&option=202" target="_blank" rel="nofollow">Brennan Paul E.;</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>Structural Genomics ConsortiumUniversity of Oxford NDMRBOld Road Campus Oxford OX3 7DQ UK;</p> <p>Structural Genomics ConsortiumUniversity of Oxford NDMRBOld Road Campus Oxford OX3 7DQ UK;</p> <p>Structural Genomics ConsortiumUniversity of Oxford NDMRBOld Road Campus Oxford OX3 7DQ UK;</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=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=peptides&option=203" rel="nofollow">peptides;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=protein–protein interactions&option=203" rel="nofollow">protein–protein interactions;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=small GTPases&option=203" rel="nofollow">small GTPases;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=small molecules&option=203" rel="nofollow">small molecules;</a> </p> <div class="translation"> 机译：药物发现;肽;蛋白质 - 蛋白质相互作用;小GTP酶;小分子; </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 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href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=李秀(审校)&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,李秀(审校)</a> <span> <a href="/journal-cn-23096/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 临床与病理杂志 </a> </span> <span> . 2020</span><span>,第006期</span> </span> </div> </li> <li> <div> <b>6. </b><a class="enjiyixqcontent" href="/academic-conference-cn_meeting-16681_thesis/020221685510.html">Rho GTPases家族及其调控分子在骨髓增生异常综合征中的表达研究</a> <b>[C]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=邵雪君&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 邵雪君</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=陈子兴&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,陈子兴</a> <span> <a href="/conference-cn-16681/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 第12届全国实验血液学会议 </a> <span> <span> . 2009</span> </span> </div> </li> <li> <div> <b>7. </b><a class="enjiyixqcontent" href="/academic-degree-domestic_mphd_thesis/02031869421.html">Rho GTP酶家族在黑素瘤细胞株中的表达及RhoD过表达对A375细胞骨架和迁移侵袭的影响及机制初探</a> <b>[A] </b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=温斯健&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 温斯健</a> <span> . 2016</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/06120111017047.html">一种GTP环水解酶1反馈调节蛋白的突变蛋白及应用</a> <b>[P]</b> . <span> 中国专利： CN108546291A </span> <span> . 2018-09-18</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/06120103860069.html">免疫相关GTP酶家族M（IRGM）的单克隆抗体及其应用</a> <b>[P]</b> . <span> 中国专利： CN111349170A </span> <span> . 2020-06-30</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130455532071.html">Methods of Identifying Substances with Potential Herbicide or Growth Regulatory Activity Using Plant Transporter Proteins, Uses of Transporter Proteins and Materials with Identifying Substances with Potential Herbicidal or Growth-Regulatory Action by Means of Vegetable Transporter Proteins, Use of Such Transporter Proteins for This Purpose, and Substances with a Herbicidal or Growth-Regulatory Action Identified by the Method)</a> <b>[P]</b> . <span> 外国专利：  KR960706639A </span> <span> . 1996-12-09</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：使用植物转运蛋白鉴定具有潜在除草剂或生长调节活性的物质的方法，转运蛋白的用途和通过植物转运蛋白鉴定具有潜在除草或生长调节作用的物质的材料，为此目的使用的这类转运蛋白和通过该方法确定具有除草或生长调节作用的物质） </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130429600881.html">COMPOUND HAVING INHIBITORY ACTIVITY ON A RHO-GTPASE CELL PROTEIN, A PROCESS FOR OBTAINING THE SAME, PHARMACEUTICAL COMPOSITIONS COMPRISION THEREOF AND A METHOD FOR THE TREATMENT OF A RHO-GTPASE CELL PROTEIN-MEDIATED CONDITION</a> <b>[P]</b> . <span> 外国专利：  EP2089409A1 </span> <span> . 2009-08-19</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：在Rho-GTPase细胞蛋白上具有抑制活性的化合物，获得相同蛋白的方法，其药物组合物的制备方法以及Rho-GTPase细胞蛋白介导的治疗方法 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130428125024.html">COMPOUND HAVING INHIBITORY ACTIVITY ON A RHO-GTPASE CELL PROTEIN, A PROCESS FOR OBTAINING THE SAME, PHARMACEUTICAL COMPOSITIONS COMPRISING THEREOF AND A METHOD FOR THE TREATMENT OF RHO-GTPASE CELL PROTEIN-MEDIATED CONDITION</a> <b>[P]</b> . <span> 外国专利：  US2009324708A1 </span> <span> . 2009-12-31</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> 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