查看“CDK2”的源代码

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            <strong>[[CDK2]]</strong>（<strong>[[Cyclin-Dependent Kinase 2]]</strong>）是一种在真核细胞周期调控中起核心作用的[[丝氨酸/苏氨酸激酶]]。作为[[CDK]]家族的重要成员，[[CDK2]]主要负责驱动细胞从<strong>[[G1期]]向[[S期]]</strong>转换，并维持[[S期]]的DNA复制进程。它通过与[[Cyclin E]]或[[Cyclin A]]结合被激活，随后磷酸化<strong>[[Rb蛋白]]</strong>（[[视网膜母细胞瘤蛋白]]），促使[[E2F]]转录因子释放。在临床实践中，[[CDK2]]的异常激活被认为是导致[[CDK4/6抑制剂]]（如[[哌柏西利]]）耐药的核心机制之一。因此，开发针对[[CDK2]]的高选择性抑制剂已成为突破乳腺癌及其他实体瘤治疗瓶颈的前沿策略。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[CDK2]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">G1/S期核心调控激酶 · 点击展开</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">染色体位置：12q13.13</div>
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                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1017</td>
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                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1771</td>
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                    <td style="padding: 10px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">P24941</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">关键伙伴</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[Cyclin E]]/[[Cyclin A]]</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;">约33kDa</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">基因变异</th>
                    <td style="padding: 12px; color: #0f172a;">[[CCNE1扩增]]致CDK2激活</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：细胞周期进程的“引擎”</h2>
    
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        [[CDK2]]通过有序的底物磷酸化，精密调控细胞从静止进入增殖状态：
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        <li style="margin-bottom: 12px;"><strong>[[G1/S]]转换：</strong>在[[G1]]晚期，[[Cyclin E]]表达增加并结合[[CDK2]]。该复合物磷酸化[[Rb蛋白]]，使其构象发生改变并从[[E2F]]转录因子上解离。随后[[E2F]]激活[[S期]]必需基因的表达。</li>
        <li style="margin-bottom: 12px;"><strong>[[S期]]维持：</strong>进入[[S期]]后，[[Cyclin A]]取代[[Cyclin E]]与[[CDK2]]结合。此阶段[[CDK2]]参与调控DNA复制起点的启动及[[组蛋白]]合成，确保基因组的精确复制。</li>
        <li style="margin-bottom: 12px;"><strong>活性阈值调控：</strong>[[CDK2]]的活性受[[CIP/KIP家族]]（如[[p21]]、[[p27]]）的负向调节。在DNA损伤时，[[p21]]上调并封锁[[CDK2]]的ATP结合口袋，引发细胞周期阻滞。</li>
        <li style="margin-bottom: 12px;"><strong>中心体复制：</strong>[[CDK2]]还参与磷酸化中心体相关蛋白，协调细胞分裂中的[[中心体]]复制周期。</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;">临床病理关联与药理矩阵</h2>

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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">病理领域</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">CDK2 相关异常</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">临床意义与干预策略</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[乳腺癌]] (HR+)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[CCNE1扩增]]或过表达</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">介导对[[CDK4/6抑制剂]]的获得性耐药，需联合[[CDK2]]抑制剂。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[卵巢癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[Cyclin E1]]高表达</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">与极差的预后相关，是目前[[CDK2]]靶向治疗的重点探索领域。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[子宫内膜癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[CDK2]]信号轴失控</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">作为[[合成致死]]策略的靶点，提高化疗敏感性。</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：针对CDK2的新一代抑制路径</h2>
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        目前针对[[CDK2]]的药物研发已从泛[[CDK]]抑制向高选择性分子演进：
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        <li style="margin-bottom: 12px;"><strong>[[高选择性抑制剂]]：</strong>如[[PF-07104091]]、[[BLU-222]]等。这些药物旨在精确结合[[CDK2]]的ATP口袋，减少对[[CDK1]]的脱靶抑制，从而显著降低胃肠道和造血毒性。</li>
        <li style="margin-bottom: 12px;"><strong>[[双重抑制]]方案：</strong>联合[[CDK2/4/6]]抑制剂，旨在从初始治疗阶段彻底封闭所有进入[[S期]]的激酶通路，防止肿瘤产生逃逸突变。</li>
        <li style="margin-bottom: 12px;"><strong>[[PROTAC]]降解技术：</strong>开发针对[[CDK2]]的[[蛋白降解靶向联合体]]（[[PROTAC]]），能够比单纯抑制活性更彻底地消除其在复合物中的支架作用。</li>
        <li style="margin-bottom: 12px;"><strong>[[伴随诊断]]价值：</strong>通过检测肿瘤组织中的[[Cyclin E]]水平或[[CDK2]]磷酸化状态，筛选能从靶向治疗中获益的精准人群。</li>
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            <li style="margin-bottom: 8px;"><strong>[[Cyclin E]]：</strong>[[CDK2]]在G1/S转换阶段的关键激活伴侣。</li>
            <li style="margin-bottom: 8px;"><strong>[[Rb蛋白]]：</strong>[[CDK2]]最重要的下游底物，细胞周期的门控蛋白。</li>
            <li style="margin-bottom: 8px;"><strong>[[CDK4/6抑制剂]]：</strong>如[[阿贝西利]]，其耐药后常伴随[[CDK2]]活性的代偿性上调。</li>
            <li style="margin-bottom: 8px;"><strong>[[p27/Kip1]]：</strong>内源性[[CDK2]]抑制蛋白，其降解常导致肿瘤恶性增殖。</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>Morgan DO. (1995).</strong> <em>Principles of CDK regulation.</em> <strong>[[Nature]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：该项经典研究建立了CDK2等激酶与Cyclin结合并受磷酸化调控的基本生物学框架。</span>
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            [2] <strong>Tadesse S, et al. (2019).</strong> <em>Targeting CDK2 in cancer: Challenges and opportunities for drug discovery.</em> <strong>[[Cell Cycle]]</strong>.<br>
            <span style="color: #475569;">[核心价值]：系统阐述了针对CDK2开发高选择性药物的必要性，尤其是在克服内分泌治疗耐药中的作用。</span>
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            [[CDK2]] 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;">关联因子</td>
                <td style="padding: 10px 15px; color: #334155;">[[Cyclin E1]]•[[Cyclin A2]]•[[RB1]]•[[E2F1]]•[[p21]]</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;">治疗药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[Dinaciclib]]•[[PF-07104091]]•[[BLU-222]]•[[阿伏西地]]</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;">[[Pfizer]]•[[Blueprint Medicines]]•[[MSD]]•[[NCI]]</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;">[[CDK2降解剂克服靶向耐药]]•[[CDK2与DNA损伤修复的交叉调控]]•[[基于超级增强子的CDK2转录调控]]</td>
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