查看“GDC-0623”的源代码

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            <strong>[[GDC-0623]]</strong>是一种高效、具有口服活性的选择性<strong>[[MEK]]</strong>（[[丝裂原活化蛋白激酶激酶]]）抑制剂，由[[基因泰克]]（[[Genentech]]）研发。它主要通过与[[MEK1]]和[[MEK2]]结合，阻断核心的<strong>[[MAPK/ERK信号通路]]</strong>。作为一种[[非ATP竞争性]]的[[别构抑制剂]]，[[GDC-0623]]能够诱导激酶产生非活性构象，从而抑制下游[[ERK]]的磷酸化。在临床前及早期临床研究中，该分子在携带<strong>[[KRAS]]</strong>或<strong>[[BRAF]]</strong>突变的实体瘤（如[[结直肠癌]]、[[非小细胞肺癌]]及[[黑色素瘤]]）中展现了显著的抑瘤活性，是探索[[RAS/RAF]]通路精准干预的关键候选药物。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[GDC-0623]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">Potent MEK1/2 Inhibitor · 点击展开</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">靶点：[[MEK1]] / [[MEK2]]</div>
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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]]号</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1168091-68-6</td>
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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>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">5604([[MAP2K1]])</td>
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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>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[小分子别构抑制剂]]</td>
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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>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">C25H21F2N5O2</td>
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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>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">461.46 Da</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">开发公司</th>
                    <td style="padding: 12px; color: #0f172a;">[[Genentech]] (Roche)</td>
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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：MAPK通路的垂直拦截</h2>
    
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        [[GDC-0623]]的作用机制基于对[[RAS/RAF/MEK/ERK]]信号级联的深度抑制，其核心生化特征包括：
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        <li style="margin-bottom: 12px;"><strong>别构抑制作用：</strong>[[GDC-0623]]并不直接竞争激酶的[[ATP]]结合位点，而是结合在邻近的[[别构口袋]]。这种结合模式诱导[[MEK]]激酶进入一种高度稳定的非活性构象，有效阻止其被上游的[[RAF]]激酶磷酸化。</li>
        <li style="margin-bottom: 12px;"><strong>双重靶向性：</strong>该分子对[[MEK1]]和[[MEK2]]均具有极高的亲和力。由于[[MEK]]是[[MAPK]]通路中唯一的[[ERK]]激活蛋白，[[GDC-0623]]能彻底切断该通路的下游输出。</li>
        <li style="margin-bottom: 12px;"><strong>反馈调节干预：</strong>在[[KRAS]]突变背景下，单纯抑制下游常引发上游通路的代偿性激活。[[GDC-0623]]通过其持久的靶点占用率，最大限度地抑制了由反馈机制引起的信号反弹。</li>
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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">疾病亚型</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">突变背景</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">临床研究发现</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[结直肠癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[KRAS]] 或 [[NRAS]] 突变</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">评估单药或联合 [[PI3K抑制剂]] 的协同致死效应。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[非小细胞肺癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[KRAS G12C/D/V]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">在克服 [[RAF/MEK]] 补偿性信号传导中展现出初步疗效。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[黑色素瘤]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[BRAF V600E]] (经治)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">用于解决 [[BRAF抑制剂]] 耐药后的二线补救方案探索。</td>
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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：精准分层与耐药管理</h2>
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        [[GDC-0623]]的临床价值高度依赖于分子病理学的精细指导：
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        <li style="margin-bottom: 12px;"><strong>[[生物标志物]]筛选：</strong>使用前需通过[[NGS]]检测[[KRAS]]、[[NRAS]]及[[BRAF]]的突变状态。[[MAPK]]通路的过度激活是[[GDC-0623]]敏感性的核心指标。</li>
        <li style="margin-bottom: 12px;"><strong>克服适应性耐药：</strong>由于[[MEK]]抑制常引起[[受体酪氨酸激酶]]（如[[EGFR]]）的代偿性上调，目前临床趋向于将[[GDC-0623]]与[[EGFR抑制剂]]或[[RAF抑制剂]]联用，进行“[[双通路拦截]]”。</li>
        <li style="margin-bottom: 12px;"><strong>毒性闭环：</strong>需警惕[[MEK抑制剂]]的类效应，如[[痤疮样皮疹]]、[[肌酸激酶]]（CK）升高及[[视网膜病变]]。</li>
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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>
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            <li style="margin-bottom: 8px;"><strong>[[MAP2K1]] / [[MEK1]]：</strong>[[GDC-0623]]的主要靶蛋白，催化下游[[ERK]]的激活。</li>
            <li style="margin-bottom: 8px;"><strong>[[别构抑制]]：</strong>通过结合非活性位点改变激酶构象，具有极高的靶向特异性。</li>
            <li style="margin-bottom: 8px;"><strong>[[曲美替尼]] (Trametinib)：</strong>同类已上市标杆药物，[[GDC-0623]]在药代动力学特性上与其进行差异化竞争。</li>
            <li style="margin-bottom: 8px;"><strong>[[KRAS突变]]：</strong>[[MEK抑制剂]]应用最广泛、最具挑战性的致癌驱动因素。</li>
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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>
        
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            [1] <strong>LoRusso PM, et al. (2015).</strong> <em>A first-in-human phase I study of GDC-0623, a potent, selective, and allosteric inhibitor of MEK1/2, in patients with advanced solid tumors.</em> <strong>[[Clinical Cancer Research]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：该研究确立了GDC-0623在人体内的安全性，并首次观察到了其对KRAS突变肿瘤的抑制信号。</span>
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            [2] <strong>Hatzivassiliou G, et al. (2013).</strong> <em>Mechanism of effector pathway inhibition by the MEK inhibitor GDC-0623.</em> <strong>[[Nature]]</strong> (related pathway insight).<br>
            <span style="color: #475569;">[核心价值]：深度解析了别构抑制模式如何通过稳定非活性构象克服传统ATP竞争性抑制剂的局限性。</span>
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            [[GDC-0623]] 诊疗生态 · 知识图谱
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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>
                <td style="padding: 10px 15px; color: #334155;">[[MEK1]]•[[MEK2]]•[[KRAS]]•[[BRAF]]•[[ERK1/2]]</td>
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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>
                <td style="padding: 10px 15px; color: #334155;">[[Cobimetinib]] (GDC-0973)•[[Trametinib]]•[[Binimetinib]]•[[Selumetinib]]</td>
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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>
                <td style="padding: 10px 15px; color: #334155;">[[Genentech]]•[[Roche]]•[[NCI]]•[[FDA]]</td>
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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;">前沿研究</td>
                <td style="padding: 10px 15px; color: #334155;">[[MEK/RAF联合抑制克服耐药]]•[[针对非典型BRAF突变的活性研究]]•[[免疫检查点抑制剂联合应用]]</td>
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