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Selumetinib - 版本历史
2026-04-21T08:46:54Z
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2026-01-16T03:20:22Z
<p>建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面</p>
<p><b>新页面</b></p><div><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;"><br />
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<strong>[[司美替尼]]</strong>（<strong>[[Selumetinib]]</strong>，商品名：<strong>[[科赛斯]]</strong>/<strong>[[Koselugo]]</strong>）是一种高效、高选择性的口服<strong>[[MEK1/2]]</strong>（[[丝裂原活化蛋白激酶激酶]]）抑制剂。它通过变构结合机制抑制[[MEK]]蛋白活性，进而阻断下游[[ERK]]磷酸化，是[[RAS/RAF/MEK/ERK]]信号通路的关键拦截者。[[司美替尼]]具有划时代的里程碑意义，它是全球首个获批用于治疗3岁及以上、伴有临床症状且无法手术切除的<strong>[[1型神经纤维瘤病]]</strong>（[[NF1]]）相关<strong>[[丛状神经纤维瘤]]</strong>（[[PN]]）的靶向药物。此外，该药在[[甲状腺癌]]及多种携带[[RAS/RAF]]突变的[[实体瘤]]中亦表现出显著的临床探索价值。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[司美替尼]]</div><br />
<div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[Selumetinib]] / [[Koselugo]] · 点击展开</div><br />
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<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;">[[Selumetinib]]分子结构及MEK结合口袋模型</div><br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[MEK1]] / [[MEK2]]</div><br />
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<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><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">606143-52-6</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[Entrez]]ID</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">5604([[MAP2K1]])</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">药物类型</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[MEK变构抑制剂]]</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子式</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">C17H15BrClFN4O3</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[分子量]]</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">457.68 Da</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">开发公司</th><br />
<td style="padding: 12px; color: #0f172a;">[[AstraZeneca]] (阿斯利康)</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 #0f172a; font-weight: bold;">分子机制：阻断MAPK信号级联</h2><br />
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[[司美替尼]]通过对[[MAPK]]通路关键节点的“精准拦截”，调节细胞的增殖、分化与存活：<br />
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<li style="margin-bottom: 12px;"><strong>变构抑制效应：</strong>[[司美替尼]]不竞争[[ATP]]结合位点，而是结合在[[MEK]]蛋白的一个[[变构口袋]]。这种结合诱导[[MEK]]产生非活性构象，阻止上游[[RAF]]对其进行磷酸化激活。</li><br />
<li style="margin-bottom: 12px;"><strong>针对NF1缺陷机制：</strong>在[[NF1]]患者中，[[神经纤维素]]（[[Neurofibromin]]）缺失导致[[RAS]]蛋白处于持续激活状态。[[司美替尼]]通过抑制[[RAS]]下游的[[MEK]]，显著降低信号过载，从而缩小[[丛状神经纤维瘤]]。</li><br />
<li style="margin-bottom: 12px;"><strong>反馈环干预：</strong>在某些突变背景下，[[MEK]]抑制会引发上游[[RTKs]]的代偿性激活。[[司美替尼]]通过高亲和力的持续锁定，最大限度抑制这种反馈性回弹。</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 #0f172a; font-weight: bold;">临床意义与应用场景</h2><br />
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<th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">适应症领域</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">分子驱动背景</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">临床表型与获益</th><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[1型神经纤维瘤病]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[NF1]] 抑癌基因失活</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[SPRINT研究]]显示 70% 患儿肿瘤缩小 ≥20%，改善疼痛及活动力。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[甲状腺癌]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[NRAS]] 或 [[BRAF]] 突变</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">增强碘-131（RAI）的再摄取能力，逆转放射碘抗性。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[低级别胶质瘤]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[BRAF]] 融合或点突变</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">作为儿童难治性脑瘤的创新靶向选择，延缓化疗需求。</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 #0f172a; font-weight: bold;">诊疗策略：从精准识别到毒性闭环</h2><br />
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[[司美替尼]]的临床管理需强调精准化与全流程安全性评价：<br />
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<li style="margin-bottom: 12px;"><strong>分子筛查：</strong>针对[[NF1]]相关肿瘤，需通过[[基因检测]]确认突变状态。对于[[实体瘤]]，[[RAS/RAF]]的突变谱决定了药效预测。</li><br />
<li style="margin-bottom: 12px;"><strong>[[皮疹]]与[[胃肠道]]管理：</strong>最常见副作用包括[[痤疮样皮疹]]及[[腹泻]]。建议使用[[局部抗生素]]或[[止泻药]]干预，多数可耐受，不需停药。</li><br />
<li style="margin-bottom: 12px;"><strong>[[眼科毒性]]监测：</strong>需警惕罕见的[[视网膜中央静脉阻塞]]（[[CRVO]]）或[[视网膜浆液性脱离]]。治疗期间应定期进行基线及随访眼科检查。</li><br />
<li style="margin-bottom: 12px;"><strong>[[肌酸激酶]]（CK）监控：</strong>司美替尼可导致[[CK]]无症状升高，需定期监测以防[[横纹肌溶解]]风险。</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 #0f172a; font-weight: bold;">关键相关概念</h2><br />
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<li style="margin-bottom: 8px;"><strong>[[1型神经纤维瘤病]] (NF1)：</strong>常染色体显性遗传病，由[[NF1]]基因缺陷引起。</li><br />
<li style="margin-bottom: 8px;"><strong>[[MEK1/2]]：</strong>[[MAPK]]通路的核心成员，[[司美替尼]]的直接作用靶点。</li><br />
<li style="margin-bottom: 8px;"><strong>[[丛状神经纤维瘤]] (PN)：</strong>[[NF1]]相关的重度良性肿瘤，具有侵袭性生长特性。</li><br />
<li style="margin-bottom: 8px;"><strong>[[曲美替尼]] (Trametinib)：</strong>同类已上市的 [[MEK]] 抑制剂，常用于 [[BRAF]] 突变的联合治疗。</li><br />
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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><br />
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[1] <strong>Gross AM, et al. (2020).</strong> <em>Selumetinib in Children with Inoperable Plexiform Neurofibromas.</em> <strong>[[The New England Journal of Medicine]]</strong>. 382(15):1430-1442.[Academic Review]<br><br />
<span style="color: #475569;">[权威点评]：SPRINT研究奠定了司美替尼在NF1领域的开创性地位，为全球首个针对此类孤儿药病症的有效方案。</span><br />
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[2] <strong>Dombi E, et al. (2016).</strong> <em>Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas.</em> <strong>[[NEJM]]</strong>.<br><br />
<span style="color: #475569;">[核心价值]：早期关键研究揭示了MEK抑制剂如何通过减缓信号传导成功实现PN病灶的容量性缩小。</span><br />
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[[司美替尼]] ([[Selumetinib]]) 诊疗生态 · 知识图谱<br />
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<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><br />
<td style="padding: 10px 15px; color: #334155;">[[MEK1]]•[[MEK2]]•[[RAS]]•[[BRAF]]•[[NF1]]•[[ERK]]</td><br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">同类/演进</td><br />
<td style="padding: 10px 15px; color: #334155;">[[曲美替尼]]•[[比尼替尼]] (Binimetinib)•[[考比替尼]] (Cobimetinib)</td><br />
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<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><br />
<td style="padding: 10px 15px; color: #334155;">[[AstraZeneca]]•[[Merck & Co.]]•[[FDA]]•[[NMPA]]</td><br />
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<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><br />
<td style="padding: 10px 15px; color: #334155;">[[针对成人NF1患者的疗效研究]]•[[针对黑色素瘤的联合免疫疗法]]•[[在皮肤型NF1中的外用制剂开发]]</td><br />
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223.160.138.164