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<strong>[[G007-LK]]</strong>是一种具有高活性和特异性的口服小分子<strong>[[端锚聚合酶]]</strong>（[[Tankyrase]]，[[TNKS]]）抑制剂。它通过竞争性结合[[TNKS1]]和[[TNKS2]]的[[烟酰胺]]结合位点，阻断底物蛋白的[[聚ADP核糖基化]]（[[PARylation]]）修饰。[[G007-LK]]最核心的生物学功能是拮抗<strong>[[Wnt/β-catenin]]</strong>信号通路：通过抑制[[TNKS]]，稳定[[Wnt]]通路负调节因子<strong>[[AXIN]]</strong>蛋白，从而促进[[β-catenin]]的降解。该分子作为研究[[Wnt]]依赖型肿瘤（如[[结直肠癌]]）和[[纤维化]]疾病的强有力工具，在精准医学领域具有重要的临床转化价值。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[G007-LK]]</div><br />
<div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[TNKS]] Inhibitor · [[Wnt]]拮抗剂 · 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;">[[G007-LK]]分子构效结合模型</div><br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[TNKS1]] / [[TNKS2]]</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;">1380672-07-0</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;">8603([[TNKS]])</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;">[[PARP家族]]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;">C23H20F3N5O2</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;">455.43 Da</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">溶解性</th><br />
<td style="padding: 12px; color: #0f172a;">易溶于[[DMSO]]</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：稳定AXIN以破坏致癌复合物</h2><br />
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[[G007-LK]]通过精准阻断[[端锚聚合酶]]的催化活性，实现对[[Wnt]]通路的深度抑制：<br />
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<li style="margin-bottom: 12px;"><strong>抑制PARylation修饰：</strong>[[TNKS]]正常情况下会对[[AXIN]]（β-catenin破坏复合物的核心骨架）进行[[聚ADP核糖基化]]修饰，标记其进入[[泛素-蛋白酶体]]途径降解。[[G007-LK]]阻断此修饰，防止[[AXIN]]被清除。</li><br />
<li style="margin-bottom: 12px;"><strong>增强破坏复合物功能：</strong>胞质内[[AXIN]]蛋白浓度的升高促进了[[破坏复合物]]（包含[[APC]]、[[GSK3β]]）的组装，使<strong>[[β-catenin]]</strong>发生磷酸化。</li><br />
<li style="margin-bottom: 12px;"><strong>切断转录级联：</strong>被磷酸化的[[β-catenin]]迅速降解，无法进入细胞核结合[[TCF/LEF]]转录因子，从而关闭[[MYC]]、[[Cyclin D1]]等促增殖基因的转录。</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;">研究应用矩阵：疾病干预潜力</h2><br />
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<th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">疾病模型</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">突变/病理基础</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">[[G007-LK]] 效应表现</th><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[结直肠癌]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[APC]] 突变驱动型</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">显著下调核内 [[β-catenin]] 水平，抑制肿瘤类器官生长。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[胰腺癌]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[Wnt]] 配体依赖型</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">减少肿瘤干细胞特性，增强化疗药物敏感性。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[器官纤维化]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">肌成纤维细胞激活</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">通过抑制 [[TNKS]] 干扰 [[Wnt]] 与 [[TGF-β]] 通路的交叉对话。</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：精准识别与毒性平衡</h2><br />
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作为高度专一的[[TNKS]]抑制剂，[[G007-LK]]的临床转化需解决通路广泛抑制带来的系统性挑战：<br />
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<li style="margin-bottom: 12px;"><strong>[[生物标志物]]驱动：</strong>主要针对[[APC]]突变导致的通路异常。对于下游[[β-catenin]]（[[CTNNB1]]）直接突变的肿瘤，[[G007-LK]]稳定上游[[AXIN]]的效果可能减弱。</li><br />
<li style="margin-bottom: 12px;"><strong>[[肠道毒性]]管理：</strong>由于正常的肠道隐窝干细胞高度依赖[[Wnt]]信号进行再生，[[G007-LK]]可能导致肠黏膜损伤。临床开发侧重于寻找[[间歇性给药]]方案以降低副作用。</li><br />
<li style="margin-bottom: 12px;"><strong>联合用药协同：</strong>探索将其与[[MEK抑制剂]]或[[PI3K抑制剂]]联用，旨在通过多信号通路垂直或平行拦截，克服单药引起的[[反馈性激活]]。</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>[[Tankyrase]] (TNKS)：</strong>[[PARP]]酶家族成员，参与调控[[Wnt]]通路、[[端粒长度]]及[[葡萄糖代谢]]。</li><br />
<li style="margin-bottom: 8px;"><strong>[[Wnt/β-catenin通路]]：</strong>经典的细胞命运决定通路，其失控是人类癌症中最常见的驱动因素之一。</li><br />
<li style="margin-bottom: 8px;"><strong>[[AXIN]]：</strong>[[β-catenin]]降解复合物的限速组分，其稳态直接决定通路活性。</li><br />
<li style="margin-bottom: 8px;"><strong>[[PARylation]]：</strong>一种可逆的蛋白质翻译后修饰，在信号转导中起到“降解标签”的作用。</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>Lau T, et al. (2013).</strong> <em>A novel tankyrase inhibitor, G007-LK, reduces Wnt/β-catenin signaling and tumor growth.</em> <strong>[[Cancer Research]]</strong>. 73(10):3132-44.[Academic Review]<br><br />
<span style="color: #475569;">[权威点评]：该项基石研究系统证明了G007-LK在动物模型中抑制APC突变型结直肠癌的效力。</span><br />
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[2] <strong>Voronkov A, et al. (2013).</strong> <em>Structural basis and SAR for G007-LK, a highly potent and selective inhibitor of tankyrase 1 and 2.</em> <strong>[[Journal of Medicinal Chemistry]]</strong>.<br><br />
<span style="color: #475569;">[核心价值]：详细阐述了G007-LK的化学优化过程及其对烟酰胺结合口袋的高选择性识别机制。</span><br />
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[[G007-LK]] 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;">关联靶点</td><br />
<td style="padding: 10px 15px; color: #334155;">[[TNKS1]]•[[TNKS2]]•[[AXIN1]]•[[β-catenin]]•[[APC]]</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;">[[XAV939]]•[[IWR-1]]•[[JW55]]•[[NVP-TNKS656]]</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;">涉及通路</td><br />
<td style="padding: 10px 15px; color: #334155;">[[经典Wnt通路]]•[[端粒保护]]•[[Hippo信号通路交叉]]</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;">[[克服TNKS抑制剂的胃肠道毒性]]•[[在免疫治疗中的增敏作用]]•[[针对神经退行性疾病的探索]]</td><br />
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