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GSK321 - 版本历史
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<strong>[[GSK321]]</strong>是一种高特异性、具有细胞活性的口服小分子<strong>[[突变型IDH1]]</strong>（[[mIDH1]]）抑制剂。由[[葛兰素史克]]（[[GSK]]）研发，该分子专门针对[[异柠檬酸脱氢酶1]]（[[IDH1]]）的常见致病突变体（如<strong>[[R132H]]</strong>、[[R132C]]及[[R132L]]）。[[GSK321]]通过别构结合机制，强效阻断突变激酶将[[α-酮戊二酸]]（[[α-KG]]）转化为致癌代谢物<strong>[[2-羟基戊二酸]]</strong>（[[2-HG]]）的过程。在临床前研究中，[[GSK321]]展现了诱导[[急性髓系白血病]]（[[AML]]）细胞分化及抑制[[神经胶质瘤]]增殖的显著效力，是研究肿瘤[[代谢重编程]]与[[表观遗传重塑]]的关键工具化合物及候选药物。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[GSK321]]</div><br />
<div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">Mutant IDH1 Inhibitor · 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;">[[GSK321]]与突变型[[IDH1]]结合口袋示意</div><br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[IDH1 R132X]]</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;">1616480-26-4</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;">3417([[IDH1]])</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;">[[小分子别构抑制剂]]</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;">C26H26N4O3S</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;">474.58 Da</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">选择性</th><br />
<td style="padding: 12px; color: #0f172a;">突变型对野生型 > 100倍</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：代谢拦截与分化重启</h2><br />
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[[GSK321]]通过高度选择性的化学结构，精准切断了由突变型[[IDH1]]介导的致癌信号级联：<br />
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<li style="margin-bottom: 12px;"><strong>抑制2-HG合成：</strong>在携带[[R132H]]突变的细胞中，[[IDH1]]获得了将[[α-KG]]还原为[[2-HG]]的异常功能。[[GSK321]]通过与激酶的[[别构位点]]结合，降低酶的催化频率，使细胞内[[2-HG]]水平迅速下降至正常范围。</li><br />
<li style="margin-bottom: 12px;"><strong>逆转[[表观遗传]]抑制：</strong>[[2-HG]]作为[[α-KG]]的竞争性抑制剂，会封锁[[TET2]]去甲基化酶和[[组蛋白去甲基化酶]]（[[KDMs]]）。使用[[GSK321]]后，这些酶的活性得以恢复，逆转了肿瘤细胞的[[DNA高甲基化]]状态。</li><br />
<li style="margin-bottom: 12px;"><strong>诱导肿瘤分化：</strong>在[[AML]]模型中，[[GSK321]]能解除由于表观遗传失控导致的“[[分化停滞]]”，促使原始白血病细胞向成熟的[[粒细胞]]或[[单核细胞]]分化，从而丧失无限增殖能力。</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;">应用图谱：核心研究方向矩阵</h2><br />
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<th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">研究领域</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">分子变异基础</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">关键效应</th><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[急性髓系白血病]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[IDH1 R132H/C]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">诱导 [[CD11b]] 表达，促进白血病细胞终末分化。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[神经胶质瘤]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[IDH1 R132H]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">抑制肿瘤细胞侵袭性，协同 [[放疗]] 或 [[烷化剂]] 化疗。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[软骨肉瘤]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">高频 [[IDH1]] 突变</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">通过耗竭 [[2-HG]] 抑制干性维持及软骨基质异常分泌。</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：基于代谢组学的精准干预</h2><br />
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[[GSK321]]的使用体现了肿瘤治疗中“[[代谢矫正]]”的思路，其临床应用逻辑包括：<br />
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<li style="margin-bottom: 12px;"><strong>分子筛查前置：</strong>应用前必须通过[[NGS]]或[[Sanger测序]]确认[[IDH1]]是否存在[[R132]]位点突变。对于野生型肿瘤，[[GSK321]]几乎无抑制活性。</li><br />
<li style="margin-bottom: 12px;"><strong>[[药效监测]]标志物：</strong>临床研究中通常利用[[LC-MS]]动态监测血浆或肿瘤组织中的<strong>[[2-HG]]</strong>水平。2-HG的显著下降是判断[[GSK321]]靶向占用成功的“金标准”。</li><br />
<li style="margin-bottom: 12px;"><strong>克服获得性耐药：</strong>长期使用可能出现[[IDH2]]代偿性突变或同一基因的其他[[顺式突变]]。目前的策略正探索[[IDH1/IDH2联合抑制]]或与[[去甲基化药物]]（如[[阿扎胞苷]]）联用。</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>[[2-羟基戊二酸]] (2-HG)：</strong>一种“致癌代谢物”，通过干扰[[α-KG]]依赖性酶类引发全基因组超甲基化。</li><br />
<li style="margin-bottom: 8px;"><strong>[[R132H]]：</strong>[[IDH1]]最常见的突变类型，常见于继发性[[胶质母细胞瘤]]。</li><br />
<li style="margin-bottom: 8px;"><strong>[[艾伏尼布]] (Ivosidenib)：</strong>全球首个获批的[[IDH1]]抑制剂，[[GSK321]]常与其在结构与药效学研究中进行对标。</li><br />
<li style="margin-bottom: 8px;"><strong>[[代谢重编程]]：</strong>肿瘤细胞改变能量获取途径以适应恶性增长的过程。</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>Zheng, B., et al. (2015).</strong> <em>Mutant IDH1 inhibitor GSK321 induces myeloid differentiation and promotes survival in IDH1-mutant AML cells.</em> <strong>[[Blood]]</strong>.[Academic Review]<br><br />
<span style="color: #475569;">[权威点评]：该项研究系统证实了GSK321作为一种表观遗传调节剂，能有效诱导白血病克隆分化，具有极高的转化医学价值。</span><br />
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[2] <strong>Okoye-Ahaneku, C. E., et al. (2014).</strong> <em>A potent and selective IDH1 mutant inhibitor with anti-tumor activity in IDH1 mutant-positive cancer cells.</em> <strong>[[ACS Medicinal Chemistry Letters]]</strong>.<br><br />
<span style="color: #475569;">[核心价值]：首次详细披露了GSK321的分子结构及其对突变型IDH1的高选择性别构抑制机制。</span><br />
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[[GSK321]] 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;">[[IDH1 R132H]]•[[IDH2]]•[[TET2]]•[[α-KG]]•[[DNMT]]</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;">同类药物</td><br />
<td style="padding: 10px 15px; color: #334155;">[[Ivosidenib]] (AG-120)•[[Enasidenib]](IDH2)•[[BAY-1436032]]</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]]</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;">[[GSK321联合低剂量化疗方案]]•[[针对脑脊液2-HG浓度的药代动力学分析]]•[[克服IDH1/2顺式突变耐药]]</td><br />
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223.160.138.164