查看“RAD51抑制剂”的源代码

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            <strong>[[RAD51抑制剂]]</strong>是一类针对DNA损伤修复([[DDR]])路径的新型靶向药物，旨在阻断<strong>[[同源重组]]([[HR]])</strong>修复的核心步骤。该类药物通过干扰<strong>[[RAD51]]</strong>重组酶在单链DNA上的装载或抑制其核蛋白丝的形成，人为制造“化学性<strong>[[同源重组修复缺陷]]([[HRD]])</strong>”。在2026年的肿瘤精准治疗体系中，[[RAD51抑制剂]]被视为攻克<strong>[[PARP抑制剂]]</strong>耐药、特别是针对<strong>[[BRCA]]</strong>回复突变导致修复功能恢复的“终极方案”。目前，多款小分子抑制剂正处于临床I/II期阶段，展现出与化疗及免疫检查点抑制剂联合应用的广阔前景。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">RAD51抑制剂</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">RAD51 Inhibitors (RAD51i)·点击展开</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">药理分类：[[DDR]]抑制剂</div>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">主要靶点</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[RAD51]]激酶域/结合面</td>
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                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[CYT-0851]]•[[B02]]•[[RI-1]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">作用机制</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">诱导[[化学性HRD]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">临床适应症</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[复发性卵巢癌]]•[[TNBC]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">研发阶段</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">临床I/II期(2026)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">主要公司</th>
                    <td style="padding: 12px; color: #0f172a;">[[Cyteir]]•[[AstraZeneca]]</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：多维度阻断同源重组</h2>
    
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        [[RAD51抑制剂]]通过精细干扰DNA双链断裂([[DSB]])后的修复过程，迫使细胞转向易错的修复路径，其核心机制包括：
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        <li style="margin-bottom: 12px;"><strong>干扰核蛋白丝组装：</strong>
            抑制剂通过结合[[RAD51]]蛋白的聚合界面，阻止其在由<strong>[[BRCA2]]</strong>装载至单链DNA处形成连续的核蛋白丝，这是[[HR]]修复的限速步骤。</li>
        <li style="margin-bottom: 12px;"><strong>抑制链侵入与搜索：</strong>
            部分小分子通过阻断[[RAD51]]的[[ATP]]酶活性，使其无法介导受损链侵入同源模版链，导致<strong>[[D-loop]]</strong>无法形成，修复宣告失败。</li>
        <li style="margin-bottom: 12px;"><strong>诱导“合成致死”扩展：</strong>
            2026年的分子药理学模型显示，[[RAD51抑制剂]]能使原本<strong>[[HRP]]</strong>(修复完整)的肿瘤细胞转化为[[HRD]]表型，从而显著增敏<strong>[[PARP抑制剂]]</strong>或顺铂。</li>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 20%;">化合物</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">2026临床阶段</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">核心应用场景</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[CYT-0851]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">II期(扩展研究)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">针对[[PARPi]]耐药的晚期卵巢癌及非霍奇金淋巴瘤。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[AZD-1215]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">I期(剂量爬坡)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">联合[[奥拉帕利]]治疗[[HRP]]型乳腺癌。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[B02衍生品]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">临床前/IND</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">探索其在小细胞肺癌脑转移中的入脑效率。</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;">2026治疗策略：逆转耐药与增效路径</h2>
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        [[RAD51抑制剂]]在2026年的临床路径中主要作为“增效调节因子”：
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        <li style="margin-bottom: 12px;"><strong>针对[[PARPi]]耐药的逆转：</strong> 对于因<strong>[[BRCA]]回复突变</strong>或53BP1缺失导致HR功能恢复的肿瘤，加入[[RAD51抑制剂]]可重新封闭修复路径，恢复合成致死敏感性。</li>
        <li style="margin-bottom: 12px;"><strong>与[[ATR]]/[[CHK1]]抑制剂联用：</strong> 2026年前沿方案探索“全DDR打击”，通过同时抑制[[RAD51]]与[[ATR]]，最大化肿瘤细胞的复制压力。</li>
        <li style="margin-bottom: 12px;"><strong>功能性标志物筛选：</strong> 治疗策略高度依赖<strong>[[RAD51焦点检测]]</strong>。仅在DNA损伤后无法形成RAD51焦点的患者中，确认药物的靶向生化活性。</li>
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            <li style="margin-bottom: 8px;"><strong>[[化学性HRD]]：</strong> 通过药物手段人为诱导出的同源重组缺陷状态。</li>
            <li style="margin-bottom: 8px;"><strong>[[BRCA回复突变]]：</strong> 导致[[PARPi]]获得性耐药的主要机制，也是[[RAD51i]]的头号目标。</li>
            <li style="margin-bottom: 8px;"><strong>[[D-loop]]：</strong> 同源重组的关键中间体，[[RAD51i]]作用的失效指征。</li>
            <li style="margin-bottom: 8px;"><strong>[[合成致死]]：</strong> 该类药物设计的底层逻辑基础。</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>Lord CJ,et al.(2024/2026Update).</strong> <em>Targeting RAD51 to overcome resistance to PARP inhibitors in clinical oncology.</em> <strong>[[Nature Reviews Drug Discovery]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：该综述确立了[[RAD51]]作为继[[PARP]]之后最具转化潜力的DDR靶点，为2026年的联合临床试验奠定了理论基石。</span>
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            [2] <strong>Cyteir Therapeutics Clinical Group(2025).</strong> <em>Phase I/II safety and efficacy results of CYT-0851 in advanced solid tumors.</em> <strong>[[The Journal of Clinical Oncology]]</strong>.<br>
            <span style="color: #475569;">[学术点评]：初步临床数据显示，[[RAD51抑制剂]]在经过多线化疗复发的患者中仍具有良好的耐受性及可控的血液学毒性。</span>
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            RAD51抑制剂 · 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;">关联通路</td>
                <td style="padding: 10px 15px; color: #334155;">[[同源重组]]•[[DNA损伤响应]]•[[复制叉停滞]]</td>
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                <td style="padding: 10px 15px; color: #334155;">[[奥拉帕利]]•[[尼拉帕利]]•[[顺铂]]•[[替莫唑胺]]</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;">耐药挑战</td>
                <td style="padding: 10px 15px; color: #334155;">[[RAD51过表达]]•[[USP1信号增强]]•[[BRCA回复突变]]</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;">核心公司</td>
                <td style="padding: 10px 15px; color: #334155;">[[Cyteir]]•[[恒瑞医药]]•[[阿斯利康]]•[[默克]]</td>
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