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GSK126 - 版本历史
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<strong>[[GSK126]]</strong>是一种高特异性、竞争性结合<strong>[[SAM]]</strong>（S-腺苷甲硫氨酸）的小分子<strong>[[EZH2]]</strong>抑制剂。作为**[[PRC2]]**（[[聚多蛋白抑制复合物2]]）核心组分的拮抗剂，[[GSK126]]能够显著降低细胞内**[[H3K27me3]]**（[[组蛋白H3第27位赖氨酸三甲基化]]）水平，从而逆转由[[EZH2]]过度活跃引起的抑癌基因沉默。在临床前研究及早期临床评估中，该分子对携带[[EZH2]]激活突变（如[[Y641]]、[[A677]]等）的<strong>[[弥漫大B细胞淋巴瘤]]</strong>（[[DLBCL]]）和<strong>[[滤泡性淋巴瘤]]</strong>（[[FL]]）展现了强效的抗肿瘤活性。作为表观遗传学研究的标杆化合物，[[GSK126]]为理解染色质重构与肿瘤发生机制提供了关键工具。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[GSK126]]</div><br />
<div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">EZH2 Selective Inhibitor · 点击展开</div><br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[EZH2]] / [[KMT6]]</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;">1346574-57-9</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;">2146([[EZH2]])</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;">[[组蛋白甲基转移酶抑制剂]]</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;">C31H39N7O2</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;">526.67 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;">[[GSK]] (葛兰素史克)</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：组蛋白密码的表观重写</h2><br />
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[[GSK126]]通过干扰染色质的封闭状态，重新激活被异常阻遏的转录程序。其生化逻辑高度精准：<br />
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<li style="margin-bottom: 12px;"><strong>SAM竞争性抑制：</strong>[[GSK126]]特异性占据[[EZH2]]激酶域内的[[SAM]]结合口袋。作为甲基供体的[[SAM]]无法结合，导致[[EZH2]]失去甲基转移酶活性。</li><br />
<li style="margin-bottom: 12px;"><strong>调控H3K27三甲基化：</strong>[[EZH2]]是负责[[H3K27]]三甲基化的唯一酶。[[GSK126]]的使用导致基因启动子区域的[[H3K27me3]]丰度下降，染色质从紧致（[[异染色质]]）状态转变为松散状态。</li><br />
<li style="margin-bottom: 12px;"><strong>恢复抑癌基因表达：</strong>在[[B细胞淋巴瘤]]中，[[EZH2]]突变常导致分化相关基因和肿瘤抑制因子的持续沉默。[[GSK126]]能够“解锁”这些基因，诱导肿瘤细胞发生[[分化]]或[[细胞凋亡]]。</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;">临床应用与病理研究矩阵</h2><br />
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<th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">疾病场景</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">EZH2 分子状态</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">[[GSK126]] 研究结论</th><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[弥漫大B细胞淋巴瘤]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[Y641]] / [[A677]] 激活突变</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">显著下调 H3K27me3，抑制生发中心衍生型淋巴瘤增殖。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[滤泡性淋巴瘤]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">EZH2 过表达或突变</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">诱导肿瘤细胞凋亡，并可能增强对化疗的敏感性。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[多发性骨髓瘤]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">PRC2 活性上调</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">临床前模型中显示出与 [[Bcl-2抑制剂]] 的协同效应。</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：从单一干预到系统重塑</h2><br />
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[[GSK126]]作为表观遗传药物的先驱，其开发过程为[[精准医疗]]提供了重要启示：<br />
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<li style="margin-bottom: 12px;"><strong>分子分层：</strong>[[GSK126]]的效力高度依赖于肿瘤的[[EZH2]]突变背景。携带[[Y641]]等激活突变的患者是其主要潜在获益人群，需配合[[NGS]]检测。</li><br />
<li style="margin-bottom: 12px;"><strong>药效学监测：</strong>由于其作用于组蛋白修饰，监测皮肤或肿瘤活检组织中[[H3K27me3]]的下降程度是评估[[靶点占用率]]（[[Target Engagement]]）的标准。</li><br />
<li style="margin-bottom: 12px;"><strong>克服耐药：</strong>长期使用可能面临[[反馈性信号补偿]]（如[[MAPK]]通路激活）。目前策略倾向于将其与[[化疗]]或[[免疫检查点抑制剂]]联用，旨在打破肿瘤的免疫抑制微环境。</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>[[EZH2]]：</strong>组蛋白甲基转移酶，肿瘤表观遗传调控的核心靶标。</li><br />
<li style="margin-bottom: 8px;"><strong>[[PRC2]]：</strong>由 [[EZH2]]、[[EED]]、[[SUZ12]] 等组成的蛋白质复合体。</li><br />
<li style="margin-bottom: 8px;"><strong>[[Tazemetostat]] (EPZ-6438)：</strong>首个获批上市的同类药物，[[GSK126]]为其重要的研发对标分子。</li><br />
<li style="margin-bottom: 8px;"><strong>[[组蛋白甲基化]]：</strong>一种动态可逆的蛋白质翻译后修饰，决定了基因组的表达开关。</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>McCabe MT, et al. (2012).</strong> <em>EZH2 inhibition as a therapeutic strategy for lymphoma with activating mutations.</em> <strong>[[Nature]]</strong>. 492(7427):108-112.[Academic Review]<br><br />
<span style="color: #475569;">[权威点评]：该项里程碑式研究首次确立了GSK126在EZH2突变淋巴瘤中的治疗概念。</span><br />
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[2] <strong>Yap DB, et al. (2011).</strong> <em>Somatic mutations at EZH2 Y641 in lymphoma enhance methyltransferase activity on monomethylated H3K27.</em> <strong>[[Blood]]</strong>.<br><br />
<span style="color: #475569;">[核心价值]：揭示了EZH2激活突变的生化本质，为GSK126等抑制剂的研发提供了分子靶标依据。</span><br />
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[[GSK126]] 调控生态 · 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;">关联因子</td><br />
<td style="padding: 10px 15px; color: #334155;">[[EZH2]]•[[H3K27me3]]•[[SAM]]•[[PRC2]]•[[EED]]</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;">[[Tazemetostat]]•[[CPI-1205]]•[[Valemetostat]]•[[Shr-2554]]</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;">[[GSK]]•[[NCI]]•[[Dana-Farber Cancer Institute]]•[[FDA]]</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;">[[EZH2抑制剂重塑免疫微环境]]•[[克服血液瘤耐药的联合用药]]•[[针对实体瘤表观遗传漏洞的探索]]</td><br />
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