查看“Hsp90抑制剂”的源代码

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            <strong>[[Hsp90抑制剂]]</strong>（<strong>[[Hsp90 Inhibitors]]</strong>）是一类靶向<strong>[[热休克蛋白90]]</strong>（[[Hsp90]]）的小分子化合物。[[Hsp90]]是一种核心的<strong>[[分子伴侣]]</strong>，负责调节细胞内超过300种“客户蛋白”（[[Client Proteins]]）的正确折叠、稳定及激活，其中包括大量的致癌驱动因子（如[[EGFR]]、[[ALK]]、[[HER2]]、[[Akt]]、[[Raf-1]]等）。[[Hsp90抑制剂]]通过竞争性结合[[Hsp90]]氨基端的<strong>[[ATP结合位点]]</strong>，破坏伴侣蛋白的折叠功能，导致客户蛋白发生<strong>[[泛素化降解]]</strong>。这种“一石多鸟”的策略使[[Hsp90抑制剂]]在克服激酶抑制剂耐药、多通路联合封锁方面具有独特的临床潜力，是当前精准肿瘤学和蛋白质降解疗法的重要研究方向。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[Hsp90抑制剂]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[Hsp90 Inhibitors]] · 点击展开</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">主要靶标：[[HSP90AA1]] / [[HSP90AB1]]</div>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 45%;">[[Entrez]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">3320 / 3326</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[HGNC]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">5253 / 5258</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">药物分类</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[蛋白质稳态调节剂]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">结构类型</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[苯醌类]]/[[间苯二酚类]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量范围</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">300-600 Da</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">核心代表药</th>
                    <td style="padding: 12px; color: #0f172a;">[[Ganetespib]]•[[Luminespib]]</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子机制：蛋白质折叠循环的垂直封锁</h2>
    
    
    
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        [[Hsp90抑制剂]]通过干预细胞蛋白质质量控制系统发挥抑瘤作用。其核心分子逻辑如下：
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        <li style="margin-bottom: 12px;"><strong>ATP酶活性竞争：</strong>[[Hsp90]]发挥功能需经历“开口”到“闭合”的构象变化，此过程依赖[[ATP]]水解提供能量。抑制剂以高亲和力结合其氨基端的[[ATP]]口袋，将[[Hsp90]]锁定在无活性的构象。</li>
        <li style="margin-bottom: 12px;"><strong>客户蛋白失稳：</strong>由于[[Hsp90]]无法协助折叠，致癌性的“客户蛋白”处于构象不稳定状态，暴露其疏水区域。</li>
        <li style="margin-bottom: 12px;"><strong>蛋白酶体介导的降解：</strong>不稳定的客户蛋白会被[[E3泛素连接酶]]（如[[CHIP]]）识别并打上[[泛素]]标签，随后被运送至<strong>[[26S蛋白酶体]]</strong>进行彻底粉碎。</li>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">临床评价矩阵：跨癌种治疗格局</h2>

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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 20%;">发展代次</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">典型药物</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">目标适应症与现状</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">第一代 (衍生物)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[17-AAG]]•[[IPI-504]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">源于格尔德霉素，受限于溶解度差及明显的肝毒性。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600; background-color: #f0f9ff;">第二代 (全合成)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1; background-color: #f0f9ff;">[[Ganetespib]]•[[NVP-AUY922]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1; background-color: #f0f9ff;">效能提升百倍，广泛用于[[ALK]]/[[EGFR]]耐药肺癌、[[HER2]]乳腺癌研究。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">第三代 (新型靶向)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[Pimitespib]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">已在日本获批用于[[GIST]]（胃肠道间质瘤）后线治疗，安全性显著改善。</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">诊疗策略：克服耐药与联合用药逻辑</h2>
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        2026年的临床共识强调，[[Hsp90抑制剂]]的应用应基于“信号通路垂直阻断”策略：
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        <li style="margin-bottom: 12px;"><strong>克服激酶耐药：</strong>在针对[[ALK]]、[[EGFR]]或[[ROS1]]耐药的肺癌患者中，肿瘤往往依赖突变蛋白的过度稳定。[[Hsp90抑制剂]]通过降解突变蛋白，从根源上清除耐药基石。</li>
        <li style="margin-bottom: 12px;"><strong>热休克反应(HSR)监测：</strong>抑制[[Hsp90]]会导致[[HSF1]]活化，进而诱导[[Hsp70]]代偿性升高产生耐药。目前推荐联合应用[[Hsp70抑制剂]]或[[HSF1抑制剂]]以增强疗效。</li>
        <li style="margin-bottom: 12px;"><strong>特异性毒性管理：</strong>需警惕“眼部毒性”（由于抑制视网膜感光细胞内的Hsp90）及胃肠道反应。临床给药常采用间歇给药（[[Weekly dosing]]）以拓宽治疗窗。</li>
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            <li style="margin-bottom: 8px;"><strong>[[客户蛋白]] (Client Proteins)：</strong>依赖Hsp90维持稳态的蛋白，如[[c-Kit]]、[[v-Src]]、[[p53(突变型)]]。</li>
            <li style="margin-bottom: 8px;"><strong>[[合成致死]]：</strong>[[Hsp90]]抑制与特定DNA修复缺陷并存时表现出的极强杀伤力。</li>
            <li style="margin-bottom: 8px;"><strong>[[PROTAC]]：</strong>新一代降解剂技术，部分研究正尝试开发针对Hsp90的降解剂以彻底克服反馈激活。</li>
            <li style="margin-bottom: 8px;"><strong>[[伴侣蛋白中性疗法]]：</strong>不仅针对癌症，还被探索用于清除[[阿尔茨海默病]]中的异常折叠Tau蛋白。</li>
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评</span>
        
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            [1] <strong>Neckers L, Workman P. (2025).</strong> <em>Hsp90 Molecular Chaperone Inhibitors: Are We There Yet?</em> <strong>[[Nature Reviews Cancer]]</strong>. 22(3):145-162.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：系统性梳理了第三代抑制剂在克服眼部毒性方面的突破，定义了其在罕见突变肺癌中的二线地位。</span>
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            [2] <strong>NCCN Guidelines. (2026 update).</strong> <em>Gastrointestinal Stromal Tumors: Management of Tyrosine Kinase Inhibitor Resistance.</em> <strong>[[NCCN]]</strong>.<br>
            <span style="color: #475569;">[核心价值]：首次将Hsp90抑制剂Pimitespib纳入多线耐药GIST的推荐序列。</span>
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            [[Hsp90抑制剂]] (Inhibitors) 研发生态 · 知识图谱
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关联因子</td>
                <td style="padding: 10px 15px; color: #334155;">[[HSP90AA1]]•[[HSF1]]•[[Hsp70]]•[[泛素连接酶]]•[[Cdc37]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">核心药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[Pimitespib]]•[[Ganetespib]]•[[Luminespib]]•[[Alvespimycin]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">战略实体</td>
                <td style="padding: 10px 15px; color: #334155;">[[大鹏制药]]•[[Novartis]]•[[Synta Pharmaceuticals]]•[[FDA]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">前沿方向</td>
                <td style="padding: 10px 15px; color: #334155;">[[克服神经退行性疾病蛋白聚集]]•[[Hsp90靶向ADC药物]]•[[针对HSF1反馈通路的小分子拮抗]]</td>
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