查看“Peposertib”的源代码

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            <strong>Peposertib</strong>（研发代号：<strong>M3814</strong>）是由德国默克（Merck KGaA）研发的一种强效、高选择性、口服 <strong>DNA-PK</strong>（DNA 依赖性蛋白激酶）抑制剂。DNA-PK 是 DNA 双链断裂（DSB）修复机制中 <strong>[[NHEJ]]</strong>（非同源末端连接）通路的关键驱动子。Peposertib 通过阻断 DNA-PK 的催化活性，使癌细胞无法修复由<strong>放射治疗</strong>或化疗（如拓扑异构酶抑制剂）造成的致命性 DNA 损伤。此外，最新的研究表明，Peposertib 还能通过诱导胞质 DNA 累积来激活 <strong>cGAS-STING</strong> 通路，增强肿瘤的免疫原性，是放疗免疫联合治疗（Radio-Immunotherapy）的重要候选药物。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Peposertib</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">M3814 / DNA-PK Inhibitor (点击展开)</div>
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                    [[Image:NHEJ_repair_mechanism_inhibition.jpg|100px|机制：阻断NHEJ介导的DSB连接]]
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心：NHEJ 通路阻断剂</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%;">研发机构</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[Merck KGaA]] (德国默克)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">核心靶点</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[DNA-PKcs]] (催化亚基)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">受阻通路</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">[[NHEJ]] (非同源末端连接)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">给药方式</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a; font-weight: bold;">口服 (PO)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">主要应用</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[放疗增敏]], 联合化疗</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">临床阶段</th>
                    <td style="padding: 6px 12px; color: #b91c1c;">Phase I/II</td>
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        细胞修复 DNA 双链断裂（DSB）主要有两条路：精准缓慢的 <strong>HR</strong>（同源重组）和快速粗糙的 <strong>NHEJ</strong>（非同源末端连接）。
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    <ul style="padding-left: 25px; color: #334155;">
        <li style="margin-bottom: 12px;"><strong>NHEJ 的主宰：</strong> 
            <br>NHEJ 是哺乳动物细胞修复 DSB 的主要方式（占 80% 以上），不依赖同源模板。<strong>DNA-PK</strong> 是 NHEJ 复合物的核心激酶，它像“胶水”一样将断裂的 DNA 末端拉在一起并进行连接。</li>
        <li style="margin-bottom: 12px;"><strong>放疗增敏机理：</strong> 
            <br>放射治疗（RT）通过制造大量的 DSB 来杀死癌细胞。癌细胞通常会上调 DNA-PK 来快速修复这些损伤，从而产生放疗抵抗。Peposertib 强效抑制 DNA-PK，让 DSB 无法修复，导致细胞在有丝分裂中死亡。</li>
        <li style="margin-bottom: 12px;"><strong>ATM/ATR 协同：</strong> 
            <br>DNA-PK 与 ATM、ATR 并称为 DDR 三大激酶。Peposertib 可与 ATM 抑制剂产生合成致死效应，全面封锁 DNA 修复网络。</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;">超越修复：免疫治疗的新搭档</h2>
    
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        <h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">cGAS-STING 激活剂</h3>
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            当 DNA-PK 被抑制时，未修复的 DNA 片段会泄漏到细胞质中。这些胞质 DNA 会被 <strong>cGAS</strong> 识别，激活 <strong>STING</strong> 通路，诱导 I 型干扰素释放。这能招募 CD8+ T 细胞，将“冷肿瘤”变“热”，从而增强 PD-1/PD-L1 抑制剂的疗效。
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">联合策略</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">合作伙伴</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">临床逻辑</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">放疗 (RT)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">Palliative RT / SBRT</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #16a34a; font-weight: bold;">放疗增敏 (Radiosensitization)</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">化疗</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">阿霉素 (Doxorubicin) / 拓扑替康</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">阻断药物诱导的 DSB 修复（DSB 诱导剂）。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">免疫治疗</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">Avelumab (PD-L1)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">利用 cGAS-STING 通路增强抗肿瘤免疫。</td>
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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 [Academic Review]</span>
        
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            [1] <strong>Zenke FT, et al. (2020).</strong> <em>Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Chemotherapy in Advanced Solid Tumors.</em> <strong>[[Clinical Cancer Research]]</strong>. <br>
            <span style="color: #475569;">[点评]：Peposertib 的基础药理学论文，全面展示了其分子结构、激酶选择性以及在体内外模型中对放疗和化疗的增敏作用。</span>
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            [2] <strong>Xue Y, et al. (2022).</strong> <em>DNA-PK inhibition synergizes with radiotherapy to induce cGAS-STING-dependent antitumor immunity.</em> <strong>[[JCI Insight]]</strong>. <br>
            <span style="color: #475569;">[点评]：揭示了 Peposertib 免疫调节机制的关键研究，证明了其通过激活 cGAS-STING 通路来增强放疗引起的抗肿瘤免疫反应。</span>
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            [3] <strong>van Bussel MTJ, et al. (2021).</strong> <em>First-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (M3814) in advanced solid tumours.</em> <strong>[[European Journal of Cancer]]</strong>. <br>
            <span style="color: #475569;">[点评]：首次人体临床试验数据，确立了口服给药的安全性、耐受性和推荐的 II 期剂量（RP2D）。</span>
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            Peposertib · 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;">上游机制</td>
                <td style="padding: 10px 15px; color: #334155;">[[DNA双链断裂]] (DSB) • [[Ku70/Ku80]] • [[放疗]]</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;">核心通路</td>
                <td style="padding: 10px 15px; color: #334155;">[[NHEJ]] (非同源末端连接) • [[cGAS-STING]]</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;">默克DDR家族</td>
                <td style="padding: 10px 15px; color: #334155;">[[Berzosertib]] (ATR, IV) • [[Tuvusertib]] (ATR, Oral)</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;">临床应用</td>
                <td style="padding: 10px 15px; color: #334155;">[[放疗增敏]] • [[直肠癌]] • [[头颈癌]]</td>
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