查看“格列替尼”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>[[格列替尼]]</strong>（<strong>[[Glesatinib]]</strong>，研发代码：<strong>[[MGCD265]]</strong>）是一种创新、口服、高选择性的多靶点酪氨酸激酶抑制剂（[[TKI]]）。它主要针对<strong>[[MET]]</strong>（[[肝细胞生长因子受体]]）、<strong>[[Axl]]</strong>、<strong>[[Ron]]</strong>以及[[VEGFR]]家族。[[格列替尼]]通过独特的Ⅱ型抑制机制结合在激酶的非活性构象上，能够有效拦截由<strong>[[MET基因扩增]]</strong>、<strong>[[MET外显子14跳跃突变]]</strong>或[[MET过表达]]驱动的信号通路。在临床研究中，[[格列替尼]]在[[非小细胞肺癌]]（[[NSCLC]]）及其他[[实体瘤]]中展现了显著的抗肿瘤活性，特别是对于解决[[第一代MET抑制剂]]（如[[克唑替尼]]）耐药后出现的[[激酶区二次突变]]具有独特的药理学优势。
        </p>
    </div>

    <div class="medical-infobox mw-collapsible mw-collapsed" style="width: 320px; float: right; margin: 0 0 25px 25px; 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%, #ffffff 100%); text-align: center; cursor: pointer;">
            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[格列替尼]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[Glesatinib]] / [[MGCD265]] · 点击展开</div>
        </div>
        
        <div class="mw-collapsible-content">
            <div style="padding: 20px; text-align: center; background-color: #f8fafc;">
                <div style="padding: 12px; border: 1px solid #e2e8f0; border-radius: 8px; background: #fff; display: inline-block;">
                    <div style="width: 140px; height: 90px; background-color: #f1f5f9; display: flex; align-items: center; justify-content: center; color: #94a3b8; font-size: 0.8em; padding: 10px; text-align: center;">[[Glesatinib]]分子结构及MET激酶结合模型</div>
                </div>
                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[MET]] / [[Axl]] / [[Ron]]</div>
            </div>

            <table style="width: 100%; border-spacing: 0; border-collapse: collapse; font-size: 0.85em;">
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 45%;">[[CAS]]登记号</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1135431-15-6</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[Entrez]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">4233([[MET]])</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">药物类型</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[Ⅱ型TKI]] (多靶点)</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子式</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">C32H25F2N5O3S2</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[分子量]]</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">629.7 Da</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">开发厂商</th>
                    <td style="padding: 12px; color: #0f172a;">[[Mirati Therapeutics]]</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;">分子机制：多靶点协同拦截</h2>
    
    <p style="margin: 15px 0; text-align: justify;">
        [[格列替尼]]通过对肿瘤细胞生长与生存轴的精准打击，抑制恶性表型：
    </p>
    
    <ul style="padding-left: 25px; color: #334155;">
        <li style="margin-bottom: 12px;"><strong>Ⅱ型抑制剂策略：</strong>与传统的Ⅰ型抑制剂（结合在激酶的活性构象）不同，[[格列替尼]]结合在激酶域的<strong>[[DFG-out]]</strong>非活性构象。这种深度结合模式能够克服部分因靶点突变产生的[[位阻耐药]]。</li>
        <li style="margin-bottom: 12px;"><strong>MET通路封锁：</strong>在[[MET]]驱动型肿瘤中，[[格列替尼]]阻断了[[HGF]]诱导的受体二聚化及自磷酸化，抑制下游[[Ras/MAPK]]和[[PI3K/Akt]]通路，诱导细胞凋亡。</li>
        <li style="margin-bottom: 12px;"><strong>克服EMT耐药：</strong>通过抑制<strong>[[Axl]]</strong>激酶，[[格列替尼]]能够逆转由[[上皮-间质转化]]（[[EMT]]）引起的传统[[EGFR-TKI]]耐药。</li>
        <li style="margin-bottom: 12px;"><strong>抗血管生成协同：</strong>对[[VEGFR]]的抑制作用不仅切断了肿瘤的血供，还能调节肿瘤微环境，增强其他疗法的渗透性。</li>
    </ul>

    <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;">临床意义与应用图谱</h2>

    <div style="overflow-x: auto; margin: 25px auto; 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: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">适应症领域</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">分子特征背景</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">临床表型与获益</th>
            </tr>
            <tr>
                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[非小细胞肺癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[MET外显子14跳跃]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">针对特定变异人群显示出显著的[[ORR]]（客观缓解率），延缓疾病进展。</td>
            </tr>
            <tr>
                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[旁路激活耐药]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">EGFR+伴MET扩增</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">联合[[奥希替尼]]，旨在攻克第三代 [[EGFR-TKI]] 耐药瓶颈。</td>
            </tr>
            <tr>
                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[其他实体瘤]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">MET通路依赖型</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">在胃癌、甲状腺癌等具有 [[MET/Axl]] 异常表达的瘤种中展现潜力。</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;">诊疗策略：精准分层与耐药管理</h2>
    <p style="margin: 15px 0; text-align: justify;">
        [[格列替尼]]的临床管理强调分子诊断前置与安全性动态监控：
    </p>
    <ul style="padding-left: 25px; color: #334155;">
        <li style="margin-bottom: 12px;"><strong>分子筛查：</strong>必须通过[[NGS]]（[[二代测序]]）或[[FISH]]明确患者的[[MET]]扩增倍数或突变位点，精准识别获益人群。</li>
        <li style="margin-bottom: 12px;"><strong>垂直联合应用：</strong>在[[旁路耐药]]场景下，[[格列替尼]]常需与其他驱动基因抑制剂联用。需关注联合用药带来的叠加毒性。</li>
        <li style="margin-bottom: 12px;"><strong>不良反应监测：</strong>常见副作用包括[[腹泻]]、[[疲劳]]及[[外周水肿]]。对于[[Ⅱ型TKI]]，需特别监测其对[[心血管]]系统（如[[QT间期]]延长）的影响。</li>
        <li style="margin-bottom: 12px;"><strong>动态耐药追踪：</strong>通过[[液体活检]]（[[ctDNA]]）监测治疗过程中出现的新的[[激酶区突变]]，为后续更换三代抑制剂提供依据。</li>
    </ul>

    <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;">关键相关概念</h2>
    <div style="background-color: #f8fafc; border: 1px solid #e2e8f0; border-radius: 8px; padding: 15px; margin: 20px 0;">
        <ul style="margin: 0; padding-left: 20px; color: #334155;">
            <li style="margin-bottom: 8px;"><strong>[[MET基因]]：</strong>定位于[[7q31]]，编码具有酪氨酸激酶活性的跨膜受体。</li>
            <li style="margin-bottom: 8px;"><strong>[[Axl激酶]]：</strong>属于[[TAM家族]]，与肿瘤耐药及免疫逃逸密切相关。</li>
            <li style="margin-bottom: 8px;"><strong>[[Ⅱ型抑制剂]]：</strong>结合在激酶“失活状态”的抑制剂，通常具有更长的靶点停留时间。</li>
            <li style="margin-bottom: 8px;"><strong>[[赛沃替尼]] (Savolitinib)：</strong>已上市的高选择性MET抑制剂，为 [[格列替尼]] 的重要对标品种。</li>
        </ul>
    </div>

    <div style="font-size: 0.92em; line-height: 1.6; color: #1e293b; margin-top: 50px; border-top: 2.2px 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;">学术参考文献与权威点评</span>
        
        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [1] <strong>Engelman JA, et al. (2017).</strong> <em>Glesatinib, a potent c-Met and Axl inhibitor, in patients with MET-driven non-small cell lung cancer.</em> <strong>[[Journal of Clinical Oncology]]</strong>. 35(15):9067.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：格列替尼在MET 14跳变及MET扩增患者中表现出了良好的靶向活性，尤其是其Ⅱ型结合机制带来的长效获益潜力。</span>
        </p>

        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [2] <strong>Gherardi E, et al. (2012).</strong> <em>Targeting MET and HGF in cancer: the way forward.</em> <strong>[[Nature Reviews Cancer]]</strong>.<br>
            <span style="color: #475569;">[核心价值]：系统性解析了MET通路的药理性干预逻辑，为格列替尼等多靶点药物的研发奠定了基础。</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;">
            [[格列替尼]] ([[Glesatinib]]) 诊疗生态 · 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; white-space: nowrap;">关联靶点</td>
                <td style="padding: 10px 15px; color: #334155;">[[MET]]•[[AXL]]•[[RON]]•[[VEGFR2]]•[[HGF]]</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; white-space: nowrap;">类似/演进</td>
                <td style="padding: 10px 15px; color: #334155;">[[卡马替尼]] (Capmatinib)•[[特泊替尼]] (Tepotinib)•[[赛沃替尼]]•[[卡博替尼]]</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; white-space: nowrap;">战略实体</td>
                <td style="padding: 10px 15px; color: #334155;">[[Mirati Therapeutics]]•[[FDA]]•[[NMPA]]•[[ASCO]]</td>
            </tr>
            <tr>
                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">研究前沿</td>
                <td style="padding: 10px 15px; color: #334155;">[[格列替尼联合免疫检查点抑制剂]]•[[针对MET D1228突变的克服研究]]•[[脑转移渗透性评估]]</td>
            </tr>
        </table>
    </div>

</div>