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<h1 style="margin: 0; color: #1e40af; font-size: 28px;">17-DMAG (Alvespimycin)</h1><br />
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<strong>17-DMAG</strong>（Alvespimycin，17-二甲氨基乙氨基-17-去甲氧基格尔德霉素）是一种半合成的苯醌安莎霉素类（Ansamycin）化合物，是 <strong>[[HSP90]]</strong> 的高效、水溶性抑制剂。作为格尔德霉素（Geldanamycin）的二代衍生物，17-DMAG 克服了母体化合物水溶性差和严重的肝毒性缺陷。它通过竞争性结合 HSP90 N 端的 <strong>ATP 结合位点</strong>，诱导多种致癌客户蛋白（如 AKT、HER2、Bcr-Abl、c-Kit 等）通过泛素-蛋白酶体途径降解，从而在多种血液肿瘤和实体瘤模型中表现出显著的抗肿瘤活性。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">17-DMAG</div><br />
<div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">Potent Water-Soluble HSP90 Inhibitor</div><br />
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<div style="font-size: 0.75em; color: #64748b; margin-top: 10px; font-weight: 600;">17-DMAG 分子结构</div><br />
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<tr style="border-bottom: 1px solid #e2e8f0;"><th style="padding: 8px; text-align: left; background-color: #f8fafc; color: #475569; width: 40%;">CAS 号</th><td style="padding: 8px; color: #0f172a;">467214-20-6</td></tr><br />
<tr style="border-bottom: 1px solid #e2e8f0;"><th style="padding: 8px; text-align: left; background-color: #f8fafc; color: #475569;">分子式</th><td style="padding: 8px; color: #0f172a;">$C_{32}H_{48}N_{4}O_{8}$</td></tr><br />
<tr style="border-bottom: 1px solid #e2e8f0;"><th style="padding: 8px; text-align: left; background-color: #f8fafc; color: #475569;">分子量</th><td style="padding: 8px; color: #0f172a;">$616.75\ g/mol$</td></tr><br />
<tr style="border-bottom: 1px solid #e2e8f0;"><th style="padding: 8px; text-align: left; background-color: #f8fafc; color: #475569;">作用靶点</th><td style="padding: 8px; color: #b91c1c; font-weight: bold;">HSP90 (α/β)</td></tr><br />
<tr style="border-bottom: 1px solid #e2e8f0;"><th style="padding: 8px; text-align: left; background-color: #f8fafc; color: #475569;">水溶性</th><td style="padding: 8px; color: #16a34a;">高（盐酸盐形式）</td></tr><br />
<tr><th style="padding: 8px; text-align: left; background-color: #f8fafc; color: #475569;">临床状态</th><td style="padding: 8px; color: #0f172a;">Phase I/II</td></tr><br />
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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: 10px; border-left: 6px solid #1e40af; font-weight: bold;">分子机制：分子伴侣功能的阻断</h2><br />
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17-DMAG 通过精确干预 <strong>HSP90 伴侣循环（Chaperone Cycle）</strong>发挥抗肿瘤效应：<br />
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<li style="margin-bottom: 12px;"><strong>ATP 口袋占据：</strong>17-DMAG 对 HSP90 N 端 ATP 口袋的亲和力（$K_d \approx 30\ nM$）远高于内源性 ATP，阻止了 ATP 的结合与水解。</li><br />
<li style="margin-bottom: 12px;"><strong>客户蛋白去稳定化：</strong>由于 HSP90 无法进入“闭合”构象来完成蛋白质折叠，其监管的“客户蛋白”（如 <strong>AKT, HER2, c-Raf</strong>）会暴露其疏水结构域。</li><br />
<li style="margin-bottom: 12px;"><strong>泛素-蛋白酶体降解：</strong>被去稳定化的蛋白会招募 <strong>[[CHIP]]</strong> 等 E3 泛素连接酶，被打上泛素标签后在 26S 蛋白酶体中降解。</li><br />
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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 #1e40af; font-weight: bold;">临床研究数据汇总</h2><br />
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<th style="padding: 12px; border: 1px solid #e2e8f0; width: 30%;">适应症</th><br />
<th style="padding: 12px; border: 1px solid #e2e8f0; width: 20%;">研究阶段</th><br />
<th style="padding: 12px; border: 1px solid #e2e8f0;">主要临床终点与观察项</th><br />
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<td style="padding: 12px; border: 1px solid #e2e8f0;"><strong>急性髓系白血病 (AML)</strong></td><br />
<td style="padding: 12px; border: 1px solid #e2e8f0;">Phase I/II</td><br />
<td style="padding: 12px; border: 1px solid #e2e8f0;">观察到外周血母细胞显著减少，伴随客户蛋白降解及代偿性 HSP70 表达上调。</td><br />
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<td style="padding: 12px; border: 1px solid #e2e8f0;"><strong>晚期实体瘤 (口服给药)</strong></td><br />
<td style="padding: 12px; border: 1px solid #e2e8f0;">Phase I</td><br />
<td style="padding: 12px; border: 1px solid #e2e8f0;">评估了最大耐受剂量 (MTD)。常见毒性包括疲劳、胃肠道反应及轻度肝酶升高。</td><br />
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<td style="padding: 12px; border: 1px solid #e2e8f0;"><strong>去势抵抗性前列腺癌</strong></td><br />
<td style="padding: 12px; border: 1px solid #e2e8f0;">Phase II</td><br />
<td style="padding: 12px; border: 1px solid #e2e8f0;">作为单药活性有限，目前研究重心转向联合放化疗方案。</td><br />
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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 #1e40af; font-weight: bold;">治疗策略与协同效应</h2><br />
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17-DMAG 目前主要的研发策略集中在<strong>联合用药</strong>以克服耐药性：<br />
<br>1. <strong>克服热休克反应：</strong>联合 HSP70 抑制剂以阻断 17-DMAG 诱导的细胞代偿性存活信号。<br />
<br>2. <strong>免疫检查点增敏：</strong>研究显示 17-DMAG 可通过重塑肿瘤微环境，降低 PD-L1 表达并增加肿瘤浸润淋巴细胞，从而增强抗 PD-1 疗法的疗效。<br />
<br>3. <strong>放疗增敏：</strong>通过以降解 DNA 损伤修复相关的客户蛋白（如 BRCA1/2）来提高放射治疗的杀伤率。<br />
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<h4 style="margin: 0 0 15px 0; color: #1e40af; font-size: 1.1em;">关键相关概念 (Key Concepts)</h4><br />
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<span style="background: #e0f2fe; padding: 5px 12px; border-radius: 20px;">● <strong>Protein Homeostasis</strong></span><br />
<span style="background: #e0f2fe; padding: 5px 12px; border-radius: 20px;">● <strong>Chaperone Addiction</strong></span><br />
<span style="background: #e0f2fe; padding: 5px 12px; border-radius: 20px;">● <strong>17-AAG (Tanespimycin)</strong></span><br />
<span style="background: #e0f2fe; padding: 5px 12px; border-radius: 20px;">● <strong>Proteasomal Degradation</strong></span><br />
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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 #1e40af; font-weight: bold;">参考文献</h2><br />
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[1] <strong>[Academic Review]</strong> Neckers L, Workman P. (2012). <em>Hsp90-targeted therapy: state of the art and future directions.</em> <strong>Clinical Cancer Research</strong>. 18(1):64-76.<br />
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[2] <strong>Pacey S, et al. (2011).</strong> <em>A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors.</em> <strong>Clinical Cancer Research</strong>. 17(6):1561-70.<br />
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[3] <strong>Saitoh M, et al. (2002).</strong> <em>17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) as a novel Hsp90 inhibitor with potent antitumor activity in vitro and in vivo.</em> <strong>Cancer Chemotherapy and Pharmacology</strong>.<br />
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<div style="font-weight: bold;">17-DMAG · 知识图谱</div><br />
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<span style="cursor: pointer; opacity: 0.9;">分子靶点</span><br />
<span style="cursor: pointer; opacity: 0.9;">代谢通路</span><br />
<span style="cursor: pointer; opacity: 0.9;">临床试验</span><br />
<span style="cursor: pointer; opacity: 0.9;">联合用药</span><br />
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