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<strong>Tuvusertib</strong>（研发代号：<strong>M1774</strong>）是由德国默克（Merck KGaA）研发的一种强效、高选择性、<strong>口服</strong> ATR 激酶抑制剂。作为新一代 ATRi 的代表，Tuvusertib 旨在克服第一代药物（如 [[Berzosertib]]）需静脉给药且药代动力学不佳的局限。它通过阻断 ATR-CHK1 信号轴，抑制 DNA 损伤检查点激活，使携带高<strong>[[复制压力]]</strong>（如 [[ATM]] 缺失或 [[ARID1A]] 突变）的癌细胞因无法修复 DNA 损伤而发生有丝分裂灾难（Mitotic Catastrophe）。目前，该药物正处于多项名为 <strong>DDRiver</strong> 的全球临床试验中，探索单药及与 [[PARP抑制剂]] 或免疫治疗联合的应用潜力。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Tuvusertib</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">M1774 / Oral ATR Inhibitor (点击展开)</div><br />
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[[Image:Tuvusertib_chemical_structure_concept.jpg|100px|口服便利性：改进的药代动力学结构]]<br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心优势：口服 / 高效能</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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<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[ATR激酶]]</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 (QD/BID)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">研发代号</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">M1774</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">临床阶段</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">Phase I/II (DDRiver)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">敏感标志物</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">[[ATM缺失]], [[ARID1A突变]]</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">主要竞品</th><br />
<td style="padding: 6px 12px; color: #0f172a;">[[Ceralasertib]], [[Camonsertib]]</td><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;">从 Berzosertib 到 Tuvusertib：进化的 ATRi</h2><br />
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ATR 抑制剂的研发经历了从静脉注射到口服的迭代。Tuvusertib 的设计初衷是为了解决第一代药物的局限性：<br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">比较维度</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">Berzosertib (M6620)</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">Tuvusertib (M1774)</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">给药途径</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>静脉注射 (IV)</strong><br>需频繁去医院，依从性差。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #16a34a; font-weight: bold;">口服 (Oral)<br>每日一次，方便长期维持。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">药效学</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">半衰期较短，靶点抑制波动大。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">生物利用度高，可实现<strong>持续稳定的靶点抑制</strong>。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">临床定位</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">主要作为化疗增敏剂（联合 Gem/Cis）。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">探索<strong>单药合成致死</strong>及与 DDRi/IO 的新型联合。</td><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;">DDRiver 临床计划：寻找精准人群</h2><br />
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<h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">DDRiver Solid Tumors 301 (NCT04170153)</h3><br />
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这是 Tuvusertib 的首次人体试验。初步结果显示，其在晚期实体瘤患者中具有良好的耐受性，且在携带 <strong>ATM 缺失</strong> 或 <strong>ARID1A 突变</strong> 的患者中观察到了明显的抗肿瘤活性（肿瘤缩小），验证了合成致死机制。<br />
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<li style="margin-bottom: 12px;"><strong>联合治疗策略：</strong> <br />
<br>默克正在积极探索 Tuvusertib 与 <strong>[[Niraparib]]</strong> (PARP 抑制剂) 的联合（DDRiver 320），旨在利用“双重阻断”策略（同时切断单链和双链修复通路）来克服 PARP 耐药。</li><br />
<li style="margin-bottom: 12px;"><strong>免疫协同：</strong> <br />
<br>ATR 抑制会导致胞质内 DNA 片段累积，激活 cGAS-STING 通路。Tuvusertib 与 <strong>[[Avelumab]]</strong> (PD-L1) 的联合试验旨在验证这一“冷肿瘤变热”的假设。</li><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>Yap TA, et al. (2024).</strong> <em>First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors.</em> <strong>[[Clinical Cancer Research]]</strong>. <br><br />
<span style="color: #475569;">[点评]：最新发表的 I 期临床数据，确立了 Tuvusertib 的推荐剂量（180 mg QD, 2周吃/1周停），并首次在临床中证实了其对 ATM/ARID1A 突变肿瘤的疗效。</span><br />
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[2] <strong>Jo U, et al. (2024).</strong> <em>The Novel ATR Inhibitor Tuvusertib (M1774) Induces Replication Protein Overexpression and Broad Synergy with DNA-targeted Anticancer Drugs.</em> <strong>[[Molecular Cancer Therapeutics]]</strong>. <br><br />
<span style="color: #475569;">[点评]：临床前药理学研究，揭示了 Tuvusertib 与拓扑异构酶抑制剂及 PARP 抑制剂广泛的协同增效作用机制。</span><br />
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[3] <strong>Merck KGaA. (2022).</strong> <em>Development Programs in Oncology: DDRiver Clinical Trials.</em> <strong>[[Merck Group Press Release]]</strong>. <br><br />
<span style="color: #475569;">[点评]：官方发布的研发战略，明确了 Tuvusertib 在默克 DDR 管线中的核心地位，接棒 Berzosertib 成为主推的 ATR 抑制剂。</span><br />
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Tuvusertib · 知识图谱<br />
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<td style="padding: 10px 15px; color: #334155;">[[Berzosertib]] (M6620, IV) • [[VX-970]]</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;">竞争对手</td><br />
<td style="padding: 10px 15px; color: #334155;">[[Ceralasertib]] (AZD6738) • [[Camonsertib]] (RP-3500) • [[Elimusertib]]</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;">合成致死</td><br />
<td style="padding: 10px 15px; color: #334155;">[[ATM缺失]] • [[ARID1A突变]] • [[RNASEH2B缺失]]</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;">联合用药</td><br />
<td style="padding: 10px 15px; color: #334155;">[[Niraparib]] (PARPi) • [[Avelumab]] (PD-L1) • [[Topotecan]]</td><br />
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