查看“17-AAG”的源代码

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        <h1 style="margin: 0; color: #1e40af; font-size: 28px;">17-DMAG (Alvespimycin)</h1>
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            <b>17-DMAG</b>（Alvespimycin）是一种高效、水溶性的半合成安莎霉素类衍生物，主要作为<b>热休克蛋白 90（Hsp90）</b>的竞争性抑制剂。它通过结合 Hsp90 的 ATP 结合口袋，阻断其分子伴侣功能，进而导致包括 AKT、HER2、Bcr-Abl 及突变型 p53 在内的多种关键致癌“客户蛋白”通过泛素-蛋白酶体途径降解。在临床前研究中，17-DMAG 表现出比其前代药物 17-AAG 更强的生物利用度和广谱抗肿瘤活性，目前正处于针对多种血液系统恶性肿瘤及实体瘤的临床评价阶段。
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            分子百科：17-DMAG
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                <span style="color: #94a3b8; font-size: 12px; font-style: italic;">[Chemical Structure Image]</span>
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                <tr style="border-bottom: 1px solid #e2e8f0;"><td style="padding: 8px; font-weight: bold; color: #1e40af;">PubChem CID</td><td style="padding: 8px;">157683</td></tr>
                <tr style="border-bottom: 1px solid #e2e8f0;"><td style="padding: 8px; font-weight: bold; color: #1e40af;">ChemSpider</td><td style="padding: 8px;">138865</td></tr>
                <tr style="border-bottom: 1px solid #e2e8f0;"><td style="padding: 8px; font-weight: bold; color: #1e40af;">Target Gene</td><td style="padding: 8px;">HSP90AA1 / HSP90AB1</td></tr>
                <tr style="border-bottom: 1px solid #e2e8f0;"><td style="padding: 8px; font-weight: bold; color: #1e40af;">Molecular Weight</td><td style="padding: 8px;">616.75 g/mol</td></tr>
                <tr style="border-bottom: 1px solid #e2e8f0;"><td style="padding: 8px; font-weight: bold; color: #1e40af;">Formulation</td><td style="padding: 8px;">HCl Salt (Water soluble)</td></tr>
                <tr><td style="padding: 8px; font-weight: bold; color: #1e40af;">Clinical Stage</td><td style="padding: 8px;">Phase I/II</td></tr>
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    <h3 style="color: #1e40af; border-left: 5px solid #1e40af; padding-left: 10px; margin-top: 0;">作用机制 (Mechanism)</h3>
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        17-DMAG 的生物学效应主要通过精准调控<b>蛋白质稳态（Proteostasis）</b>实现：
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        <li><b>ATP 竞争性抑制：</b>17-DMAG 以纳米级亲和力（$K_d \approx 30\ nM$）结合 Hsp90 N-末端的 ATP 结合域，阻止其辅助蛋白复合物的循环。</li>
        <li><b>客户蛋白降解：</b>受抑制后，Hsp90 无法维持其“客户蛋白”（如激酶、转录因子）的折叠状态，导致其被 E3 泛素连接酶标记并递送至 26S 蛋白酶体降解。</li>
        <li><b>诱导细胞凋亡：</b>由于同时下调了 $AKT$ 和 $Bcl-2$ 等存活通路，肿瘤细胞被迫启动程序性死亡。</li>
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    <h3 style="color: #1e40af; border-left: 5px solid #1e40af; padding-left: 10px;">临床数据汇总 (Clinical Data)</h3>
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                <th style="padding: 10px; border-right: 1px solid #e2e8f0;">疾病类型</th>
                <th style="padding: 10px; border-right: 1px solid #e2e8f0;">给药方案</th>
                <th style="padding: 10px;">主要结果/毒性 (DLT)</th>
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                <td style="padding: 10px; border: 1px solid #e2e8f0;">急性髓系白血病 (AML)</td>
                <td style="padding: 10px; border: 1px solid #e2e8f0;">IV, 2次/周</td>
                <td style="padding: 10px; border: 1px solid #e2e8f0;">外周血母细胞显著减少，伴随 Hsp70 诱导。</td>
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                <td style="padding: 10px; border: 1px solid #e2e8f0;">晚期实体瘤</td>
                <td style="padding: 10px; border: 1px solid #e2e8f0;">口服/静脉</td>
                <td style="padding: 10px; border: 1px solid #e2e8f0;">常见毒性：腹泻、疲劳、天冬氨酸氨基转移酶升高。</td>
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    <h3 style="color: #1e40af; border-left: 5px solid #1e40af; padding-left: 10px;">治疗策略 (Treatment Strategy)</h3>
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        鉴于单药治疗中可能出现的耐药性，目前的研究重点转向<b>联合治疗</b>方案：
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        <li><b>克服 HSR 反应：</b>17-DMAG 与 Hsp70 抑制剂联合使用，防止代偿性热休克反应增强细胞存活。</li>
        <li><b>增敏免疫治疗：</b>近期研究表明，17-DMAG 可通过降低肿瘤细胞 PD-L1 表达及重塑骨髓衍生抑制细胞（MDSCs），增强抗 PD-1 疗效。</li>
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        <h4 style="margin: 0 0 10px 0; color: #1e40af;">关键相关概念 (Key Concepts)</h4>
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            <span>● <b>Geldanamycin Derivatives</b></span>
            <span>● <b>Protein Homeostasis</b></span>
            <span>● <b>Chaperone Addiction</b></span>
            <span>● <b>26S Proteasome</b></span>
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    <h3 style="color: #1e40af; border-left: 5px solid #1e40af; padding-left: 10px;">参考文献 (References)</h3>
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        <li><b>[Academic Review]</b> Neckers, L., & Workman, P. (2012). Hsp90-targeted therapy: state of the art and future directions. <i>Clinical Cancer Research</i>, 18(1), 64-76.</li>
        <li>Trepel, J., et al. (2010). Targeting the dynamic HSP90 complex in cancer. <i>Nature Reviews Cancer</i>, 10(8), 537-549.</li>
        <li>Lancet, J. E., et al. (2010). Phase I/II study of 17-DMAG in patients with acute myeloid leukemia. <i>Leukemia & Lymphoma</i>, 51(8), 1467-1475.</li>
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        <div style="font-weight: bold;">知识图谱导航</div>
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            <span style="cursor: pointer; opacity: 0.9;">分子靶点</span>
            <span style="cursor: pointer; opacity: 0.9;">代谢通路</span>
            <span style="cursor: pointer; opacity: 0.9;">药效评估</span>
            <span style="cursor: pointer; opacity: 0.9;">不良反应</span>
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