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<p><b>新页面</b></p><div><div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff; max-width: 1200px; margin: auto;"><br />
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<strong>[[Adavosertib]]</strong>，研发代码为<strong>[[AZD1775]]</strong>（原MK-1775），是一种首创（First-in-class）、高选择性、口服小分子<strong>[[WEE1激酶抑制剂]]</strong>。作为[[DNA损伤反应]]([[DDR]])途径的核心调节剂，Adavosertib通过抑制WEE1激酶，强制带有DNA损伤或[[TP53]]突变的肿瘤细胞跳过<strong>[[G2/M期]]细胞周期检查点</strong>而直接进入有丝分裂，导致<strong>[[有丝分裂灾难]]</strong>。目前，该药物在针对[[CCNE1]]扩增型卵巢癌、子宫浆液性癌及多种[[TP53]]突变实体瘤的联合治疗中展现出显著的抗肿瘤活性。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Adavosertib (AZD1775)</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">WEE1 Inhibitor · 核心参数</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; border-radius: 8px;">Structure: Selective WEE1 Kinase Inhibition</div><br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶标：[[WEE1]]</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%;">[[Entrez]] ID</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">7465</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[HGNC]] 符号</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">WEE1</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[UniProt]]</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">P30291</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;">500.6 g/mol</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: #0f172a;">小分子抑制剂</td><br />
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<td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">954648-33-4</td><br />
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<th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">常用剂量</th><br />
<td style="padding: 8px 12px; color: #1e40af; font-weight: bold;">临床探索性给药</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：打破细胞周期刹车</h2><br />
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Adavosertib通过精准打击DNA损伤修复路径中的关键激酶WEE1，实现对肿瘤细胞的清除：<br />
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<li style="margin-bottom: 12px;"><strong>强制有丝分裂进阶：</strong> WEE1正常生理功能是磷酸化并抑制[[CDK1]]。Adavosertib抑制WEE1后，CDK1被过度激活，强制未完成DNA修复的肿瘤细胞进入有丝分裂，诱发凋亡。</li><br />
<li style="margin-bottom: 12px;"><strong>[[合成致死]]效应：</strong> 在[[TP53]]突变的癌细胞中，G1/S检查点已失能，Adavosertib进一步剥夺其唯一的G2/M修复缓冲时间，达成选择性杀伤。</li><br />
<li style="margin-bottom: 12px;"><strong>克服复制应激：</strong> 该药可加速复制叉推进，使存在[[CCNE1]]扩增或[[MYC]]过表达的细胞因DNA损伤累积而死亡。</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;">核心临床方案矩阵</h2><br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 30%;">联合方案</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">关键适应症</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">临床价值评价</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">Adavosertib + [[吉西他滨]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">铂类耐药型高级别浆液性卵巢癌。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">显著延长无进展生存期（PFS），尤其是CCNE1扩增患者。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">Adavosertib + [[奥拉帕利]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">PARP抑制剂耐药后的实体瘤。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">协同抑制DDR通路，探索克服PARP抑制剂耐药。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">Adavosertib + [[卡铂]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">TP53突变的三阴性乳腺癌。</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">增强细胞毒性药物的DNA损伤效应，提高客观缓解率。</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;">治疗策略与安全性管理</h2><br />
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<li style="margin-bottom: 12px;"><strong>毒性管理：</strong> 主要副作用包括血液学毒性（中性粒细胞及血小板减少）和胃肠道反应。临床常采用间歇给药（如每周给药3-5天）以控制骨髓抑制。</li><br />
<li style="margin-bottom: 12px;"><strong>标志物筛选：</strong> 疗效预测依赖于精确的分子分型，[[CCNE1]]扩增、[[TP53]]突变以及[[SLFN11]]表达水平是目前重点关注的生物标志物。</li><br />
<li style="margin-bottom: 12px;"><strong>药物相互作用：</strong> Adavosertib主要通过[[CYP3A4]]代谢，需严格注意与强效CYP3A4诱导剂或抑制剂的合用。</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;">[[WEE1激酶]]</li><br />
<li style="margin-bottom: 8px;">[[合成致死]]</li><br />
<li style="margin-bottom: 8px;">[[G2/M自检点]]</li><br />
<li style="margin-bottom: 8px;">[[有丝分裂灾难]]</li><br />
<li style="margin-bottom: 8px;">[[DNA损伤反应(DDR)]]</li><br />
<li style="margin-bottom: 8px;">[[CCNE1扩增]]</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>Lheureux S, et al. (2021).</strong> <em>Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a randomised, phase 2 trial.</em> <strong>[[The Lancet]]</strong>.<br><br />
<span style="color: #475569;">[学术点评]：该项II期研究证实了WEE1抑制剂在难治性卵巢癌中的疗效，标志着该领域的重要突破。</span><br />
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[2] <strong>Do K, et al. (2015).</strong> <em>Phase I study of AZD1775 in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors.</em> <strong>[[Journal of Clinical Oncology]]</strong>.<br><br />
<span style="color: #475569;">[学术点评]：作为早期的联合用药探索，该研究为后期WEE1抑制剂的剂量优化奠定了基础。</span><br />
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Adavosertib (AZD1775) 诊疗生态 · 知识图谱<br />
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<td style="width: 90px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">关联靶点</td><br />
<td style="padding: 10px 15px; color: #334155;">[[WEE1]]•[[CDK1]]•[[TP53]]•[[CCNE1]]•[[ATR]]</td><br />
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<td style="width: 90px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">联用药物</td><br />
<td style="padding: 10px 15px; color: #334155;">[[奥拉帕利]]•[[吉西他滨]]•[[卡铂]]•[[Ceralasertib]]</td><br />
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<td style="width: 90px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">战略实体</td><br />
<td style="padding: 10px 15px; color: #334155;">[[AstraZeneca]]•[[FDA]]•[[NMPA]]•[[EMA]]</td><br />
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<td style="width: 90px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">研究前沿</td><br />
<td style="padding: 10px 15px; color: #334155;">[[克服PARPi耐药]]•[[复制应激定量化]]•[[间歇给药模型]]•[[浆液性癌精准分型]]</td><br />
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