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Peposertib - 版本历史
2026-04-18T07:47:14Z
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2026-01-28T08:04:54Z
<p>建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面</p>
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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。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Peposertib</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">M3814 / DNA-PK Inhibitor (点击展开)</div><br />
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[[Image:NHEJ_repair_mechanism_inhibition.jpg|100px|机制：阻断NHEJ介导的DSB连接]]<br />
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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><br />
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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><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[Merck KGaA]] (德国默克)</td><br />
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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><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[DNA-PKcs]] (催化亚基)</td><br />
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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><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">[[NHEJ]] (非同源末端连接)</td><br />
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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><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a; font-weight: bold;">口服 (PO)</td><br />
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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><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[放疗增敏]], 联合化疗</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">临床阶段</th><br />
<td style="padding: 6px 12px; color: #b91c1c;">Phase I/II</td><br />
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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）。<br />
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<li style="margin-bottom: 12px;"><strong>NHEJ 的主宰：</strong> <br />
<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><br />
<li style="margin-bottom: 12px;"><strong>放疗增敏机理：</strong> <br />
<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><br />
<li style="margin-bottom: 12px;"><strong>ATM/ATR 协同：</strong> <br />
<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><br />
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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><br />
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<h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">cGAS-STING 激活剂</h3><br />
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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。<br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">联合策略</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">合作伙伴</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">临床逻辑</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">放疗 (RT)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Palliative RT / SBRT</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #16a34a; font-weight: bold;">放疗增敏 (Radiosensitization)</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">化疗</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">阿霉素 (Doxorubicin) / 拓扑替康</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">阻断药物诱导的 DSB 修复（DSB 诱导剂）。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">免疫治疗</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Avelumab (PD-L1)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">利用 cGAS-STING 通路增强抗肿瘤免疫。</td><br />
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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><br />
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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><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><br />
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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><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><br />
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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><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><br />
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Peposertib · 知识图谱<br />
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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><br />
<td style="padding: 10px 15px; color: #334155;">[[DNA双链断裂]] (DSB) • [[Ku70/Ku80]] • [[放疗]]</td><br />
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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><br />
<td style="padding: 10px 15px; color: #334155;">[[NHEJ]] (非同源末端连接) • [[cGAS-STING]]</td><br />
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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><br />
<td style="padding: 10px 15px; color: #334155;">[[Berzosertib]] (ATR, IV) • [[Tuvusertib]] (ATR, Oral)</td><br />
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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><br />
<td style="padding: 10px 15px; color: #334155;">[[放疗增敏]] • [[直肠癌]] • [[头颈癌]]</td><br />
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