查看“IPI-504”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>[[IPI-504]]</strong>（通用名：<strong>[[Retaspimycin]]</strong>）是一种创新、强效且具有水溶性的口服/静脉注射型小分子<strong>[[Hsp90抑制剂]]</strong>。作为[[格尔德霉素]]（[[Geldanamycin]]）的衍生物，[[IPI-504]]通过特异性结合并抑制热休克蛋白90（[[Hsp90]]）的ATP酶活性，引发其介导的多种关键癌源性“客户蛋白”（如[[EGFR]]、[[ALK]]、[[HER2]]、[[Akt]]及[[Raf-1]]）发生<strong>[[泛素化降解]]</strong>。临床上，该药主要针对携带[[ALK重排]]或[[EGFR突变]]的<strong>[[非小细胞肺癌]]</strong>（[[NSCLC]]）、[[胃肠道间质瘤]]（[[GIST]]）以及[[转移性乳腺癌]]开展研究。尽管其在部分试验中表现出显著的分子靶向活性，但由于临床终点收益及潜在毒性风险，其研发过程为蛋白质稳态调节疗法提供了宝贵的循证医学经验。
        </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;">[[IPI-504]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[Retaspimycin]] / [[Hsp90]]抑制剂 · 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;">[[IPI-504]]分子构型与Hsp90结合模型图</div>
                </div>
                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[HSP90AA1]] (3320)</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%;">[[Entrez]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">3320([[HSP90]])</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[UniProt]]</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">P07900</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;">[[小分子靶向药]]</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;">499.6 Da</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">研发代号</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[IPI-504]] / [[BSI-201]]</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">原研厂商</th>
                    <td style="padding: 12px; color: #0f172a;">[[Infinity Pharmaceuticals]]</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;">药理机制：蛋白质折叠的下游“毁灭”</h2>
    
    
    <p style="margin: 15px 0; text-align: justify;">
        [[IPI-504]]的作用机制不同于传统的激酶抑制剂，它通过靶向伴侣蛋白系统实现对多重致癌通路的“全面封锁”：
    </p>
    <ul style="padding-left: 25px; color: #334155;">
        <li style="margin-bottom: 12px;"><strong>ATP结合位点阻断：</strong>[[IPI-504]]竞争性地结合[[Hsp90]]分子氨基端的[[ATP]]结合口袋。由于[[Hsp90]]必须依赖[[ATP]]水解释放的能量来折叠和稳定其客户蛋白，药物的结合导致该过程终止。</li>
        <li style="margin-bottom: 12px;"><strong>多靶点客户蛋白降解：</strong>一旦[[Hsp90]]功能受阻，其负责保护的蛋白质（如突变型[[EGFR]]、[[ALK]]融合蛋白、[[HER2]]等）会因构象不稳定而被细胞内的[[E3泛素连接酶]]标记。</li>
        <li style="margin-bottom: 12px;"><strong>蛋白酶体途径：</strong>被标记的客户蛋白最终通过<strong>[[26S蛋白酶体]]</strong>途径被彻底降解，从而实现单一药物对多个生存信号轴（[[PI3K/Akt]]、[[MAPK]]等）的垂直打击。</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;">临床评价矩阵：IPI-504 治疗概况</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;">分子标志物</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">临床研究结论</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;">[[ALK重排]] / [[EGFR突变]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">在 [[ALK]] 阳性患者中观察到部分缓解，但在总生存期显著获益方面存在挑战。</td>
            </tr>
            <tr>
                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[胃肠道间质瘤]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[c-Kit]] / [[PDGFR]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">探索用于[[伊马替尼]]耐药患者，但由于严重的毒性反应导致部分研究终止。</td>
            </tr>
            <tr>
                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[乳腺癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[HER2]] 阳性</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">与[[曲妥珠单抗]]联用，旨在通过降解受体蛋白克服其抗体耐药性。</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：精准选择与安全性权衡</h2>
    <p style="margin: 15px 0; text-align: justify;">
        针对[[IPI-504]]等[[Hsp90抑制剂]]的应用，临床策略侧重于“通路全覆盖”与“毒性管理”：
    </p>
    <ul style="padding-left: 25px; color: #334155;">
        <li style="margin-bottom: 12px;"><strong>优势人群筛选：</strong>由于[[Hsp90]]对不稳定的突变蛋白（如[[ALK]]融合、[[T790M]]突变）具有更强的依赖性，此类患者更易从[[IPI-504]]治疗中获益。</li>
        <li style="margin-bottom: 12px;"><strong>毒性闭环监控：</strong>研究中发现[[IPI-504]]可能导致[[转氨酶升高]]（肝毒性）及[[间质性肺炎]]。临床应用期间需密切监测血生化指标与肺功能。</li>
        <li style="margin-bottom: 12px;"><strong>序贯治疗方案：</strong>在针对[[ALK]]耐药肺癌的治疗中，[[IPI-504]]常作为二/三线尝试，以“清洗”肿瘤细胞对单一激酶抑制剂的依赖。</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>[[Hsp90]]：</strong>分子伴侣，协助新合成或突变蛋白达到功能性折叠。</li>
            <li style="margin-bottom: 8px;"><strong>[[客户蛋白]] (Client Proteins)：</strong>依赖 Hsp90 稳定的蛋白质，多为致癌因子。</li>
            <li style="margin-bottom: 8px;"><strong>[[17-AAG]]：</strong>首个进入临床的 Hsp90 抑制剂，[[IPI-504]] 是其改进后的水溶性形式。</li>
            <li style="margin-bottom: 8px;"><strong>[[热休克反应]]：</strong>抑制 Hsp90 可能诱导 Hsp70 等应激蛋白代偿性升高，导致耐药。</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>Sequist LV, et al. (2010).</strong> <em>First-in-human phase I study of retaspimycin hydrochloride (IPI-504) in patients with advanced solid tumors.</em> <strong>[[Journal of Clinical Oncology]]</strong>. 28(33):4953-60.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：揭示了 IPI-504 在人体内的药代动力学特性，初步确立了针对 ALK 阳性 NSCLC 的疗效依据。</span>
        </p>

        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [2] <strong>Gunturu KS, et al. (2013).</strong> <em>Retaspimycin hydrochloride (IPI-504) in oncology: A comprehensive review.</em> <strong>[[OncoTargets and Therapy]]</strong>.<br>
            <span style="color: #475569;">[核心价值]：系统性总结了该药在多癌种中的临床结局及其在克服激酶耐药方面的理论价值。</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;">
            [[IPI-504]] ([[Retaspimycin]]) 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;">关联因子</td>
                <td style="padding: 10px 15px; color: #334155;">[[Hsp90]]•[[HSP90AA1]]•[[EGFR]]•[[ALK]]•[[Akt]]•[[mTOR]]</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;">竞争/同类</td>
                <td style="padding: 10px 15px; color: #334155;">[[Ganetespib]]•[[17-AAG]]•[[Luminespib]]•[[Alvespimycin]]</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;">[[Infinity Pharmaceuticals]]•[[FDA]]•[[NCI]]</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;">[[克服耐药性的联合用药探索]]•[[新型非格尔德霉素类Hsp90抑制剂]]•[[伴侣蛋白作为治疗靶点的再评价]]</td>
            </tr>
        </table>
    </div>

</div>