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Dinaciclib - 版本历史
2026-04-17T03:39:09Z
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2026-01-16T02:16:06Z
<p>建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面</p>
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<strong>[[迪那西利]]</strong>（<strong>[[Dinaciclib]]</strong>）是一种创新的、高选择性的口服或静脉给药的小分子<strong>[[细胞周期蛋白依赖性激酶]]</strong>（[[CDK]]）抑制剂。该药物最初由[[默沙东]]（[[MSD]]）开发，能够强效抑制<strong>[[CDK1]]</strong>、<strong>[[CDK2]]</strong>、<strong>[[CDK5]]</strong>和<strong>[[CDK9]]</strong>。与第一代泛[[CDK]]抑制剂（如[[阿伏西地]]）相比，[[迪那西利]]展现了更优的靶向精确度和治疗窗。其核心生物学效应在于通过抑制[[CDK1/2]]诱导细胞周期阻滞，并利用对[[CDK9]]的抑制作用阻断[[转录延伸]]，进而导致促生存蛋白<strong>[[MCL-1]]</strong>迅速耗尽。目前，[[迪那西利]]在<strong>[[慢性淋巴细胞白血病]]</strong>（[[CLL]]）、[[多发性骨髓瘤]]（[[MM]]）及多种[[实体瘤]]的临床研究中表现出显著的诱导凋亡活性。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[迪那西利]]</div><br />
<div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[Dinaciclib]] / [[SCH727965]] · 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;">[[Dinaciclib]]分子结构模型</div><br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[CDK1]]/[[2]]/[[5]]/[[9]]</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;">779353-01-4</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;">1017([[CDK2]])</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;">[[小分子激酶抑制剂]]</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;">C18H20N6O2</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;">396.44 Da</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">开发公司</th><br />
<td style="padding: 12px; color: #0f172a;">[[默沙东]] / [[Tolero]]</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：多靶点拦截驱动通路</h2><br />
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[[迪那西利]]通过其精妙的分子构效，在多个层面瓦解肿瘤细胞的生存防御系统：<br />
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<li style="margin-bottom: 12px;"><strong>抑制CDK1与CDK2：</strong> [[迪那西利]]能够阻断[[细胞周期]]由[[G1]]向[[S]]期、[[G2]]向[[M]]期的转换，直接终止肿瘤细胞的增殖。</li><br />
<li style="margin-bottom: 12px;"><strong>阻断转录延伸（CDK9轴）：</strong> [[CDK9]]是转录延伸复合物[[P-TEFb]]的关键组分。[[迪那西利]]抑制[[CDK9]]可导致<strong>[[RNA聚合酶II]]</strong>失活，使得具有短半衰期的促生存基因如<strong>[[MCL-1]]</strong>和<strong>[[MYC]]</strong>的转录迅速中断。</li><br />
<li style="margin-bottom: 12px;"><strong>诱导线粒体凋亡：</strong> 由于[[MCL-1]]蛋白的快速耗减，细胞内促凋亡蛋白（如[[BIM]]、[[BAX]]）的抑制被解除，触发[[线粒体膜电位]]崩溃和[[凋亡小体]]形成。</li><br />
<li style="margin-bottom: 12px;"><strong>调控CDK5活性：</strong> 虽然[[CDK5]]在神经系统中功能显著，但在某些实体瘤中，抑制[[CDK5]]可干扰肿瘤细胞的迁移和[[骨架重塑]]。</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;">核心临床研究矩阵</h2><br />
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<th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">临床研究</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">适应症/人群</th><br />
<th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">当前临床结论</th><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[III期对照研究]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">复发难治性 [[CLL]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">与[[奥法木单抗]]相比，显著延长了中位 [[PFS]] 并提高了缓解率。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[联合方案探索]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">复发性 [[多发性骨髓瘤]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">联合[[硼替佐米]]及[[地塞米松]]在晚期患者中观察到深度应答。</td><br />
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<td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[实体瘤II期]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">[[三阴性乳腺癌]]</td><br />
<td style="padding: 8px; border: 1px solid #cbd5e1;">探索其在抑制 [[MYC]] 高表达肿瘤中的临床获益。</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：序贯方案与毒性管理</h2><br />
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[[迪那西利]]的应用需建立在严密的血流动力学和血液学监测基础之上：<br />
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<li style="margin-bottom: 12px;"><strong>[[血液学毒性]]监测：</strong> [[迪那西利]]最常见的不良反应为[[中性粒细胞减少]]，临床需根据[[ANC]]水平进行颗粒细胞集落刺激因子（[[G-CSF]]）支持或剂量调整。</li><br />
<li style="margin-bottom: 12px;"><strong>协同[[BCL-2抑制剂]]：</strong> 针对[[Venetoclax]]耐药的患者，[[迪那西利]]通过降低[[MCL-1]]水平可有效“引爆”凋亡阈值，产生强效的[[协同致死]]效应。</li><br />
<li style="margin-bottom: 12px;"><strong>[[肿瘤溶解综合征]]预防：</strong> 鉴于其快速杀伤白血病细胞的能力，高瘤负荷患者需严格执行[[水化]]、[[碱化]]及[[降尿酸]]治疗流程。</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>[[CDK9]]：</strong> 控制mRNA转录延伸的关键激酶，是[[迪那西利]]实现转录抑制的核心靶标。</li><br />
<li style="margin-bottom: 8px;"><strong>[[MCL-1]]：</strong> 一种极具抗性的抗凋亡蛋白，其水平下降是评估[[迪那西利]]药效的分子生物标志。</li><br />
<li style="margin-bottom: 8px;"><strong>[[P-TEFb]]：</strong> 正转录延伸因子b复合物，负责启动基因组的高效转录。</li><br />
<li style="margin-bottom: 8px;"><strong>[[细胞周期检查点]]：</strong> 肿瘤细胞逃避监管的机制，[[迪那西利]]通过抑制CDKs重置这些卡口。</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>Gojo I, et al. (2013).</strong> <em>A phase 1 study of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in hematologic malignancies.</em> <strong>[[Cancer Chemotherapy and Pharmacology]]</strong>.[Academic Review]<br><br />
<span style="color: #475569;">[权威点评]：该项研究首次确定了迪那西利在血液肿瘤患者中的临床安全剂量及初步疗效信号。</span><br />
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[2] <strong>Paruch K, et al. (2010).</strong> <em>Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases.</em> <strong>[[ACS Medicinal Chemistry Letters]]</strong>.<br><br />
<span style="color: #475569;">[核心价值]：系统阐述了该药物的分子设计逻辑，解析了其对特定CDK亚型的高选择性基础。</span><br />
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[[迪那西利]] ([[Dinaciclib]]) 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;">[[CDK1]]•[[CDK2]]•[[CDK5]]•[[CDK9]]•[[MCL-1]]•[[MYC]]</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;">竞争/同类</td><br />
<td style="padding: 10px 15px; color: #334155;">[[阿伏西地]] (Alvocidib)•[[Palbociclib]]•[[阿贝西利]] (Abemaciclib)</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;">[[默沙东]] (MSD)•[[Tolero Pharmaceuticals]]•[[FDA]]</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BCL-2抑制剂耐药方案研究]]•[[针对转录依赖性实体瘤的精准打击]]•[[新型口服剂型开发]]</td><br />
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