查看“Naquotinib”的源代码

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            <strong>Naquotinib</strong>（研发代码：<strong>ASP8273</strong>）是一种高选择性、不可逆的第三代<strong>[[表皮生长因子受体]]</strong>（EGFR）酪氨酸激酶抑制剂（<strong>[[TKI]]</strong>）。它旨在攻克由第一代 TKI 治疗后产生的 <strong>[[T790M]]</strong> 获得性耐药突变，同时覆盖 EGFR 敏感突变（如 Exon 19 del、L858R）。尽管其在早期临床中展现了针对非小细胞肺癌（NSCLC）的药理活性，但由于全球临床研究中的获益风险比评估，其开发历程为后续 EGFR 靶向药物的迭代提供了宝贵的经验。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Naquotinib</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px;">Drug: ASP8273 · 点击展开详情</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">第三代 EGFR-TKI</div>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">主要靶点</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>EGFR (T790M)</strong></td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">CAS 登记号</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">1448383-35-6</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子式</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">C28H32ClN7O2</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0;">534.05 Da</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">给药途径</th>
                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">口服</td>
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                    <th style="text-align: left; padding: 10px 12px; background-color: #f1f5f9; color: #475569;">研发公司</th>
                    <td style="padding: 10px 12px;">安斯泰来 (Astellas)</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;">核心机制：共价抑制与突变选择性</h2>
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        Naquotinib 展现了第三代 EGFR 抑制剂的典型药理特征，其设计的核心在于解决耐药挑战：
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        <li style="margin-bottom: 12px;"><strong>不可逆共价结合：</strong> 该分子通过与 EGFR 激酶结构域 Cys797 残基形成共价键，产生持久的酶抑制作用。</li>
        <li style="margin-bottom: 12px;"><strong>克服 T790M 耐药：</strong> 能够有效绕过第一代 TKI 无法结合的门控突变（Gatekeeper mutation），抑制耐药克隆。</li>
        <li style="margin-bottom: 12px;"><strong>野生型节省：</strong> 在生化水平上，对野生型（WT）EGFR 的选择性显著优于突变型，理论上可减轻皮疹及腹泻风险。</li>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">试验阶段</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">主要结论</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">当前地位</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">Phase I/II (Japan)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">在 T790M 阳性患者中表现出显著的 ORR。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">药理学验证成功。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">SOLAR (Phase III)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">一线治疗 NSCLC 对比第一代 TKI。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">因获益不明显及安全性提前终止。</td>
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        <li style="margin-bottom: 12px;"><strong>剂量限制性毒性：</strong> 临床实践中需严密监测胃肠道毒性（如严重腹泻）以及潜在的神经毒性。</li>
        <li style="margin-bottom: 12px;"><strong>耐药监测：</strong> 尽管可抑制 T790M，但需警惕后续出现的 <strong>[[C797S]]</strong> 等三代 TKI 共同耐药位点。</li>
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        <h3 style="margin-top: 0; color: #0f172a; font-size: 1.15em; margin-bottom: 20px; border-bottom: 2px solid #3b82f6; display: inline-block; padding-bottom: 5px;">关键相关概念</h3>
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            <div style="color: #334155;"><strong style="color: #1e40af;">[[奥希替尼]]</strong>：同类首个获批药物，目前三代 TKI 的基准。</div>
            <div style="color: #334155;"><strong style="color: #1e40af;">[[T790M]]</strong>：EGFR 突变肺癌最主要的获得性耐药机制。</div>
            <div style="color: #334155;"><strong style="color: #1e40af;">[[不可逆抑制]]</strong>：ASP8273 通过共价结合实现的药效动力学特征。</div>
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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>Goto K, et al. (2018).</strong> <em>Phase I Study of ASP8273 in Japanese Patients with NSCLC.</em> <strong>[[Journal of Thoracic Oncology]]</strong>.<br>
            <span style="color: #475569;">[学术点评]：确定了该药物在日本肺癌人群中的最大耐受剂量与初步疗效。</span>
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            [2] <strong>Yu HA, et al. (2017).</strong> <em>ASP8273 in Patients with EGFR-Mutant NSCLC: Phase 1 Results.</em> <strong>[[Journal of Thoracic Oncology]]</strong>.<br>
            <span style="color: #475569;">[学术点评]：揭示了 ASP8273 在克服 T790M 耐药中的分子临床表现。</span>
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            Naquotinib (ASP8273) · 知识图谱导航
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                <td style="width: 100px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 15px; text-align: left; vertical-align: middle;">相关靶点</td>
                <td style="padding: 10px 15px; color: #334155; text-align: left;">[[EGFR]] • [[T790M]] • [[Cys797]] • [[HER2]]</td>
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                <td style="width: 100px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 15px; text-align: left; vertical-align: middle;">对比药物</td>
                <td style="padding: 10px 15px; color: #334155; text-align: left;">[[奥希替尼]] • [[阿美替尼]] • [[伏美替尼]] • [[拉扎替尼]]</td>
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                <td style="width: 100px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 15px; text-align: left; vertical-align: middle;">研究历程</td>
                <td style="padding: 10px 15px; color: #334155; text-align: left;">[[SOLAR 试验]] • [[不可逆抑制]] • [[耐药管理]]</td>
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