查看“GDC-0879”的源代码

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            <strong>[[GDC-0879]]</strong>是一种具有口服活性、高效且高选择性的小分子<strong>[[BRAF]]</strong>激酶抑制剂（$IC_{50}$约为0.13nM）。由[[基因泰克]]（[[Genentech]]）研发，该分子主要针对携带<strong>[[BRAF V600E]]</strong>突变体的肿瘤细胞。通过竞争性结合[[BRAF]]激酶结构域的[[ATP]]结合口袋，[[GDC-0879]]能够阻断下游[[MEK]]和[[ERK]]的磷酸化级联反应，从而抑制肿瘤细胞的增殖并诱导凋亡。作为**[[MAPK信号通路]]**研究的重要工具化合物，它在解析[[BRAF]]驱动的[[黑色素瘤]]及[[结直肠癌]]的分子机制中发挥了关键作用。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[GDC-0879]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">Selective BRAF Inhibitor · 点击展开</div>
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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;">[[GDC-0879]]分子化学结构模型</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">靶点：[[BRAF V600E]]</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]]登记号</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">905230-75-7</td>
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                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">673([[BRAF]])</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[HGNC]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1097</td>
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                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">P15056</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;">353.33Da</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">抑制常数</th>
                    <td style="padding: 12px; color: #0f172a;">$IC_{50}$ = 0.13nM</td>
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        [[GDC-0879]]通过其独特的小分子构型，在[[MAPK]]信号通路中实现了精准的垂直拦截：
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        <li style="margin-bottom: 12px;"><strong>选择性ATP竞争：</strong>[[GDC-0879]]能够以极高的亲和力结合在[[BRAF]]激酶的活性位点。由于它对[[V600E]]突变体的亲和力远高于其他激酶，因此能在较低浓度下实现抑瘤效应。</li>
        <li style="margin-bottom: 12px;"><strong>抑制下游磷酸化：</strong>通过抑制[[BRAF]]活性，[[GDC-0879]]直接阻断了[[MEK]]蛋白的激活（磷酸化）。级联反应的停滞导致核内转录因子的输出减少，从而触发[[G1期]]细胞周期停滞。</li>
        <li style="margin-bottom: 12px;"><strong>差异化效应：</strong>与某些广谱激酶抑制剂不同，[[GDC-0879]]在[[BRAF]]野生型且存在[[RAS]]突变的细胞中可能表现出“[[矛盾性激活]]”，这一特性促使临床研究更加侧重于特定基因背景的筛选。</li>
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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">研究领域</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">分子变异背景</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">[[GDC-0879]]效应</th>
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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]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">诱导显著的细胞凋亡，抑制异种移植模型的肿瘤生长。</td>
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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;">[[BRAF]]突变型</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">降低[[ERK]]信号强度，联合[[EGFR抑制剂]]展现协同效应。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[甲状腺癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[BRAF]]激活突变</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">抑制肿瘤细胞侵袭性，恢复碘摄取相关基因表达。</td>
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        针对[[GDC-0879]]的研发经验为后续[[BRAF]]抑制剂的开发提供了重要参考：
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        <li style="margin-bottom: 12px;"><strong>分子分层前置：</strong>应用前必须通过[[NGS]]确认是否存在[[BRAF V600E]]突变。对于[[BRAF]]野生型或非[[V600]]位点突变，其敏感性大幅下降。</li>
        <li style="margin-bottom: 12px;"><strong>克服获得性耐药：</strong>长期使用抑制剂常引发[[旁路激活]]（如[[EGFR]]或[[HGF/MET]]上调）。目前的策略侧重于将[[GDC-0879]]等抑制剂与[[MEK抑制剂]]联合使用，实现“[[垂直抑制]]”。</li>
        <li style="margin-bottom: 12px;"><strong>反馈环阻断：</strong>在结直肠癌中，[[BRAF]]抑制会引起[[EGFR]]的反馈性激活。通过[[GDC-0879]]联合[[西妥昔单抗]]可以有效解决这一反馈性耐药。</li>
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            <li style="margin-bottom: 8px;"><strong>[[BRAF V600E]]：</strong>[[BRAF]]基因最常见的激酶活化突变，是[[GDC-0879]]的主要打击靶点。</li>
            <li style="margin-bottom: 8px;"><strong>[[维罗非尼]] (Vemurafenib)：</strong>已上市的标杆[[BRAF抑制剂]]，与[[GDC-0879]]具有类似的药理逻辑。</li>
            <li style="margin-bottom: 8px;"><strong>[[MAPK/ERK信号通路]]：</strong>调控细胞生长、分化和存活的核心信号级联。</li>
            <li style="margin-bottom: 8px;"><strong>[[矛盾性激活]] (Paradoxical Activation)：</strong>指[[BRAF抑制剂]]在[[RAS]]突变细胞中反而诱导[[RAF二聚化]]并激活信号。</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>Hoeflich KP, et al. (2009).</strong> <em>Antitumor Activity of a Novel BRAF Inhibitor, GDC-0879, in Cancer Cell Lines and Xenograft Models.</em> <strong>[[Cancer Research]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：该项基石研究系统证明了GDC-0879在V600E突变背景下的高效能，定义了其作为高选择性BRAF抑制剂的地位。</span>
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            [2] <strong>Wong H, et al. (2009).</strong> <em>Preclinical Characterization of GDC-0879, a Potent and Selective B-RAF Kinase Inhibitor.</em> <strong>[[Molecular Cancer Therapeutics]]</strong>.<br>
            <span style="color: #475569;">[核心价值]：详细披露了GDC-0879的药代动力学特性及对突变型激酶的高度专一性。</span>
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            [[GDC-0879]] 调控生态 · 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;">[[BRAF V600E]]•[[MEK1/2]]•[[ERK1/2]]•[[EGFR]]•[[KRAS]]</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/竞争</td>
                <td style="padding: 10px 15px; color: #334155;">[[维罗非尼]]•[[达拉非尼]] (Dabrafenib)•[[恩考非尼]] (Encorafenib)</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;">研究前沿</td>
                <td style="padding: 10px 15px; color: #334155;">[[克服矛盾性激活的新型RAF抑制剂]]•[[联合PI3K/mTOR抑制剂增敏研究]]•[[针对非V600E突变的亚型研究]]</td>
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