查看“Tuvusertib”的源代码

<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff; max-width: 1200px; margin: auto;">

    <div style="margin-bottom: 30px; border-bottom: 1.2px solid #e2e8f0; padding-bottom: 25px;">
        <p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;">
            <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。
        </p>
    </div>

    <div class="medical-infobox mw-collapsible mw-collapsed" style="width: 100%; max-width: 320px; margin: 0 auto 35px auto; border: 1.2px solid #bae6fd; border-radius: 12px; background-color: #ffffff; box-shadow: 0 8px 20px rgba(0,0,0,0.05); overflow: hidden;">
        
        <div style="padding: 15px; color: #1e40af; background: linear-gradient(135deg, #e0f2fe 0%, #bae6fd 100%); text-align: center; cursor: pointer;">
            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Tuvusertib</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">M1774 / Oral ATR Inhibitor (点击展开)</div>
        </div>
        
        <div class="mw-collapsible-content">
            <div style="padding: 25px; text-align: center; background-color: #f8fafc;">
                <div style="display: inline-block; background: #ffffff; border: 1px solid #e2e8f0; border-radius: 12px; padding: 20px; box-shadow: 0 4px 10px rgba(0,0,0,0.04);">
                    [[Image:Tuvusertib_chemical_structure_concept.jpg|100px|口服便利性：改进的药代动力学结构]]
                </div>
                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心优势：口服 / 高效能</div>
            </div>

            <table style="width: 100%; border-spacing: 0; border-collapse: collapse; font-size: 0.85em;">
                <tr>
                    <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>
                </tr>
                <tr>
                    <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;">[[ATR激酶]]</td>
                </tr>
                <tr>
                    <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 (QD/BID)</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">研发代号</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">M1774</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">临床阶段</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">Phase I/II (DDRiver)</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">敏感标志物</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">[[ATM缺失]], [[ARID1A突变]]</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">主要竞品</th>
                    <td style="padding: 6px 12px; color: #0f172a;">[[Ceralasertib]], [[Camonsertib]]</td>
                </tr>
            </table>
        </div>
    </div>

    <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>
    
    <p style="margin: 15px 0; text-align: justify;">
        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：
    </p>

    <div style="overflow-x: auto; margin: 30px auto; max-width: 95%;">
        <table style="width: 100%; border-collapse: collapse; border: 1.2px solid #cbd5e1; font-size: 0.9em; text-align: left;">
            <tr style="background-color: #f8fafc; border-bottom: 2px solid #0f172a;">
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">比较维度</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">Berzosertib (M6620)</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">Tuvusertib (M1774)</th>
            </tr>
            <tr>
                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">给药途径</td>
                <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>
                <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>
            </tr>
            <tr>
                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">药效学</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">半衰期较短，靶点抑制波动大。</td>
                <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>
            </tr>
            <tr>
                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">临床定位</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">主要作为化疗增敏剂（联合 Gem/Cis）。</td>
                <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>
            </tr>
        </table>
    </div>

    <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>
    
    <div style="background-color: #f0f9ff; border-left: 5px solid #1e40af; padding: 15px 20px; margin: 20px 0; border-radius: 4px;">
        <h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">DDRiver Solid Tumors 301 (NCT04170153)</h3>
        <p style="margin-bottom: 0; text-align: justify; font-size: 0.95em; color: #334155;">
            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。
        </p>
    </div>

    <ul style="padding-left: 25px; color: #334155;">
        <li style="margin-bottom: 12px;"><strong>联合治疗策略：</strong> 
            <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>
        <li style="margin-bottom: 12px;"><strong>免疫协同：</strong> 
            <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>
    </ul>

    <div style="font-size: 0.92em; line-height: 1.6; color: #1e293b; margin-top: 50px; border-top: 2px solid #0f172a; padding: 15px 25px; background-color: #f8fafc; border-radius: 0 0 10px 10px;">
        <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>
        
        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [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>
            <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>
        </p>

        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [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>
            <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>
        </p>

        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [3] <strong>Merck KGaA. (2022).</strong> <em>Development Programs in Oncology: DDRiver Clinical Trials.</em> <strong>[[Merck Group Press Release]]</strong>. <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>
        </p>
    </div>

    <div style="margin: 40px 0; border: 1px solid #e2e8f0; border-radius: 8px; overflow: hidden; font-family: 'Helvetica Neue', Arial, sans-serif; font-size: 0.9em;">
        <div style="background-color: #eff6ff; color: #1e40af; padding: 8px 15px; font-weight: bold; text-align: center; border-bottom: 1px solid #dbeafe;">
            Tuvusertib · 知识图谱
        </div>
        <table style="width: 100%; border-collapse: collapse; background-color: #ffffff;">
            <tr style="border-bottom: 1px solid #f1f5f9;">
                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">前代药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[Berzosertib]] (M6620, IV) • [[VX-970]]</td>
            </tr>
            <tr style="border-bottom: 1px solid #f1f5f9;">
                <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>
                <td style="padding: 10px 15px; color: #334155;">[[Ceralasertib]] (AZD6738) • [[Camonsertib]] (RP-3500) • [[Elimusertib]]</td>
            </tr>
            <tr style="border-bottom: 1px solid #f1f5f9;">
                <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>
                <td style="padding: 10px 15px; color: #334155;">[[ATM缺失]] • [[ARID1A突变]] • [[RNASEH2B缺失]]</td>
            </tr>
            <tr>
                <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>
                <td style="padding: 10px 15px; color: #334155;">[[Niraparib]] (PARPi) • [[Avelumab]] (PD-L1) • [[Topotecan]]</td>
            </tr>
        </table>
    </div>

</div>