查看“伊帕色替”的源代码

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            <strong>[[伊帕色替]]</strong>（<strong>[[Ipatasertib]]</strong>）是一种高选择性、口服的小分子泛<strong>[[AKT]]</strong>抑制剂，由[[基因泰克]]（[[Genentech]]）研发。它通过竞争性结合[[AKT]]（包括[[AKT1]]、[[AKT2]]和[[AKT3]]亚型）的[[ATP]]结合位点，精准阻断<strong>[[PI3K/AKT/mTOR]]</strong>信号通路的传导。该通路在多种人类癌症中因<strong>[[PTEN]]</strong>缺失、<strong>[[PIK3CA]]</strong>突变或<strong>[[AKT1]]</strong>活化而异常过度激活。临床上，[[伊帕色替]]主要用于治疗<strong>[[三阴性乳腺癌]]</strong>（[[TNBC]]）及<strong>[[转移性去势抵抗性前列腺癌]]</strong>（[[mCRPC]]），是目前针对[[AKT]]靶点最先进的候选药物之一，旨在通过精准打击细胞生存枢纽，克服传统化疗或内分泌治疗的耐药性。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[伊帕色替]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[Ipatasertib]] / [[GDC-0068]] · 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;">[[Ipatasertib]]分子结构及AKT激酶结合示意图</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶点：[[AKT1]] / [[AKT2]] / [[AKT3]]</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%;">[[Entrez]]ID</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">207([[AKT1]]) / 208</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[CAS]]登记号</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1001264-89-6</td>
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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>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[Pan-AKT抑制剂]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[UniProt]]</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">P31749 / P31751</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;">457.9 Da</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">开发公司</th>
                    <td style="padding: 12px; color: #0f172a;">[[Genentech]] / [[Roche]]</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：深度瓦解生存信号通路</h2>
    
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        [[伊帕色替]]通过干扰[[PI3K/AKT]]轴这一癌症代谢与增殖的核心中枢发挥作用。其生化机制可概括为：
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        <li style="margin-bottom: 12px;"><strong>ATP竞争性抑制：</strong>[[伊帕色替]]以极高的亲和力占据[[AKT]]激酶域的[[ATP]]结合口袋，阻止其对底物（如[[PRAS40]]、[[GSK3β]]）的磷酸化。</li>
        <li style="margin-bottom: 12px;"><strong>反馈抑制对抗：</strong>在 [[PTEN]] 缺失或 [[PIK3CA]] 突变的肿瘤中，$AKT$ 通路处于恒定激活状态。[[伊帕色替]]能有效阻断该通路驱动的抗凋亡信号，从而诱导肿瘤细胞进入[[程序性死亡]]。</li>
        <li style="margin-bottom: 12px;"><strong>通路垂直拦截：</strong>通过抑制 $AKT$，药物同步下调了下游的 $mTORC1$ 活性，限制了癌细胞的蛋白质合成与能量代谢，同时增强了对化疗药物的敏感性。</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;">临床评价矩阵：关键研究与适应症</h2>

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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">临床试验名称</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">适应症及联用方案</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">关键分子获益特征</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[LOTUS]] (Ph 2)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[三阴性乳腺癌]] + [[紫杉醇]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">显著延长 [[PFS]]，特别是在含有 [[PIK3CA/AKT1/PTEN]] 变异的亚群中。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[IPATential150]] (Ph 3)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[前列腺癌]] + [[阿比特龙]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">证实其在 [[PTEN]] 缺失型 [[mCRPC]] 患者中可显著改善放射学无进展生存。</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[IPATunity130]] (Ph 3)</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[HR+/HER2-乳腺癌]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">探索其在激素受体阳性伴 [[PIK3CA]] 突变患者中的协同效能。</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：基于生物标志物的精准选择</h2>
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        [[伊帕色替]]的使用代表了“分层医疗”的典型逻辑，其应用需严格遵循以下路径：
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        <li style="margin-bottom: 12px;"><strong>分子标志物预筛：</strong>必须通过[[NGS]]（[[二代测序]]）或[[IHC]]检测确认患者是否存在<strong>[[PTEN蛋白缺失]]</strong>或<strong>[[PIK3CA/AKT1突变]]</strong>。这是判断其获益概率的最核心依据。</li>
        <li style="margin-bottom: 12px;"><strong>不良反应管理：</strong>最常见的副作用包括[[腹泻]]、[[高血糖]]及[[皮疹]]。由于 $AKT$ 涉及胰岛素信号传导，糖尿病或糖耐量异常患者需在用药期间严密监测血糖。</li>
        <li style="margin-bottom: 12px;"><strong>垂直联合用药：</strong>鉴于 $AKT$ 抑制后可能引发的代偿性 $EGFR$ 或 $AR$ 信号上调，临床常将其与化疗（[[紫杉醇]]）或内分泌药物（[[阿比特龙]]、[[氟维司群]]）联用。</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;">关键相关概念</h2>
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            <li style="margin-bottom: 8px;"><strong>[[AKT1]]：</strong>又称[[蛋白质激酶B]]，是调节生长、生存和代谢的主开关基因。</li>
            <li style="margin-bottom: 8px;"><strong>[[PTEN]]：</strong>肿瘤抑制基因，其缺失会导致 [[PIP3]] 积聚，进而使 [[AKT]] 发生失控性活化。</li>
            <li style="margin-bottom: 8px;"><strong>[[Capivasertib]]：</strong>另一种已获批的同类 [[AKT]] 抑制剂，为伊帕色替的主要对标药物。</li>
            <li style="margin-bottom: 8px;"><strong>[[合成致死]]：</strong>[[AKT]] 抑制与特定 DNA 修复通路缺陷共存时产生的致命抑瘤效应。</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>Kim SB, et al. (2017).</strong> <em>Ipatasertib plus paclitaxel versus placebo plus paclitaxel in metastatic triple-negative breast cancer (LOTUS): a randomised phase 2 trial.</em> <strong>[[The Lancet Oncology]]</strong>. 18(10):1360-1372.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：LOTUS研究首次证明了AKT抑制剂在TNBC领域通过生物标志物分层获益的可能性。</span>
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        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [2] <strong>de Bono JS, et al. (2021).</strong> <em>Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a randomised phase 3 trial.</em> <strong>[[The Lancet]]</strong>. 398(10297):315-327.<br>
            <span style="color: #475569;">[核心价值]：确立了PTEN缺失状态作为mCRPC患者应用伊帕色替的关键筛选指标。</span>
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            [[伊帕色替]] (Ipatasertib) 诊疗生态 · 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;">关联通路</td>
                <td style="padding: 10px 15px; color: #334155;">[[PI3K]]•[[AKT]]•[[mTOR]]•[[GSK3B]]•[[FoxO]]•[[PRAS40]]</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;">治疗场景</td>
                <td style="padding: 10px 15px; color: #334155;">[[mCRPC]]•[[TNBC]]•[[HR+ Breast Cancer]]•[[胃癌(PIK3CA+)]]</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]]•[[FDA]]•[[ESMO]]</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;">前沿方向</td>
                <td style="padding: 10px 15px; color: #334155;">[[克服内分泌耐药的联合治疗]]•[[针对脑转移的渗透性研究]]•[[新型AKT降解剂开发]]</td>
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