查看“Onatasertib”的源代码

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            <strong>[[Onatasertib]]</strong>，研发代码为<strong>[[CC-223]]</strong>，是一种由[[塞尔基因]]([[Celgene]]，现属[[BMS]])研发的强效、口服、高选择性<strong>[[mTORC1/mTORC2双重抑制剂]]</strong>。作为第二代[[mTOR抑制剂]]，[[Onatasertib]]通过ATP竞争性抑制<strong>[[mTOR]]</strong>激酶活性，不仅能阻断由[[mTORC1]]介导的蛋白合成，还能有效克服第一代[[雷帕霉素]]类似物（[[Rapalogs]]）引起的[[AKT]]反馈性激活。临床上主要针对<strong>[[晚期实体瘤]]</strong>、<strong>[[非小细胞肺癌]]</strong>及<strong>[[非霍奇金淋巴瘤]]</strong>（[[NHL]]）进行开发。其独特的双重阻断机制为破解[[PI3K/AKT/mTOR通路]]异常激活导致的肿瘤耐药提供了重要策略。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Onatasertib (CC-223)</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">奥纳色替·mTORC1/2 Inhibitor·点击展开</div>
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                <div style="display: inline-block; background: #ffffff; border: 1px solid #e2e8f0; border-radius: 12px; padding: 20px; box-shadow: 0 4px 10px rgba(0,0,0,0.04);">
                     <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;">Onatasertib Structure: ATP-competitive dual mTOR inhibitor</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心靶标：mTOR (FRAP1)</div>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">[[Entrez]]ID</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">2475([[MTOR]])</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[HGNC]]ID</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">3942</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[UniProt]]</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">P42345</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">404.4 g/mol</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">给药途径</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">口服 (Daily)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">常见毒性</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">高血糖、腹泻、皮疹</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">研究热点</th>
                    <td style="padding: 12px; color: #0f172a;">克服[[雷帕霉素]]耐药</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：深度阻断 mTORC 信号复合体</h2>
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        [[Onatasertib]]作为第二代激酶抑制剂，其作用机制较第一代抑制剂（如[[依维莫司]]）更为彻底：
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        <li style="margin-bottom: 12px;"><strong>ATP 竞争性抑制：</strong> 不同于别构抑制剂，Onatasertib 直接作用于 <strong>[[mTOR]]</strong> 的激酶结构域 ATP 结合口袋，全面抑制 <strong>[[mTORC1]]</strong> 和 <strong>[[mTORC2]]</strong> 的活性。</li>
        <li style="margin-bottom: 12px;"><strong>消除反馈通路：</strong> 传统的 mTORC1 抑制会诱导 [[IGF-1R]] 介导的 <strong>[[AKT]] (Ser473)</strong> 磷酸化反馈性升高。[[Onatasertib]] 通过抑制 mTORC2 阻断了这一反馈通路，从而更深地抑制细胞增殖。</li>
        <li style="margin-bottom: 12px;"><strong>抑制下游效应子：</strong> 该药能高效下调 <strong>[[4E-BP1]]</strong> 的磷酸化和 <strong>[[p70S6K]]</strong> 的活性，从转录翻译水平协同抑制肿瘤细胞生长。</li>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">试验阶段/名称</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">目标人群</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">关键数据/结论</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[Phase I Study]] (CC-223-ST-001)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">晚期实体瘤、多发性骨髓瘤。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">确立了 <strong>45mg QD</strong> 的推荐剂量；在 <strong>[[非小细胞肺癌]]</strong> 患者中观察到初步应答。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[B细胞淋巴瘤]] 队列</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">复发或难治性 [[NHL]]。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>[[弥漫大B细胞淋巴瘤]]</strong> 患者显示出较高的代谢缓解率。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">安全性特征</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">全人群汇总分析。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">主要的 3 级以上副反应为 <strong>[[高血糖]] (20%以上)</strong> 和腹泻。</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：代谢毒性管控与精准筛选</h2>
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        [[Onatasertib]] 的临床应用需重点关注其作为广谱通路抑制剂带来的<strong>[[脱靶效应]]</strong>：
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        <li style="margin-bottom: 12px;"><strong>血糖管理策略：</strong> 由于 mTORC2 抑制会干扰胰岛素信号传导，患者常出现明显的<strong>[[高血糖]]</strong>。临床实践中建议在给药前控制基线血糖，并联合使用 [[二甲双胍]] 等降糖药。</li>
        <li style="margin-bottom: 12px;"><strong>分子标记物筛选：</strong> 携带 <strong>[[PTEN缺失]]</strong>、<strong>[[PIK3CA突变]]</strong> 或 <strong>[[AKT扩增]]</strong> 的肿瘤对 Onatasertib 往往更为敏感，建议在用药前进行基因检测。</li>
        <li style="margin-bottom: 12px;"><strong>耐药序贯考量：</strong> 对于第一代 mTOR 抑制剂耐药的患者，Onatasertib 作为二线救治方案具有理论优势。</li>
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            <li style="margin-bottom: 8px;"><strong>[[mTORC2]]：</strong> 调控 AKT Ser473 位点磷酸化的核心复合体，是 Onatasertib 的核心靶标之一。</li>
            <li style="margin-bottom: 8px;"><strong>[[PI3K/AKT/mTOR]]通路：</strong> 肿瘤中最常发生变异的增殖通路，Onatasertib 在此通路的远端节点进行精准打击。</li>
            <li style="margin-bottom: 8px;"><strong>[[依维莫司]] (Everolimus)：</strong> 代表性的第一代 mTOR 抑制剂，可作为 Onatasertib 的临床对照。</li>
            <li style="margin-bottom: 8px;"><strong>[[PTEN]]：</strong> 负调节 PI3K 通路的抑癌基因，其功能的缺失往往预示着更好的药物反应。</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>Bendell JC, et al. (2015).</strong> <em>Phase I, open-label, dose-escalation, and expansion study of the dual mTORC1/mTORC2 inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.</em> <strong>[[Cancer]]</strong>.<br>
            <span style="color: #475569;">[权威点评]：该研究定义了 Onatasertib 的剂量边界，并首次证明了双重抑制剂在多种实体瘤中的临床可行性。</span>
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            [2] <strong>Soria JC, et al. (2017).</strong> <em>CC-223, a potent and selective inhibitor of mTORC1 and mTORC2, in patients with advanced solid tumors.</em> <strong>[[Clinical Cancer Research]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[学术点评]：详细阐述了 Onatasertib 对 PI3K 通路的药理动力学抑制作用，是理解第二代 mTOR 抑制剂临床药理的重要文献。</span>
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            Onatasertib (CC-223) 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;">关联靶点</td>
                <td style="padding: 10px 15px; color: #334155;">[[mTOR]]•[[AKT]]•[[p70S6K]]•[[4E-BP1]]•[[PIK3CA]]•[[PTEN]]</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;">直接竞品</td>
                <td style="padding: 10px 15px; color: #334155;">[[AZD2014]] (Vistusertib)•[[MLN0128]] (Sapanisertib)•[[依维莫司]]</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;">[[BMS]]•[[Celgene]]•[[SinoCellGene协作]]•[[FDA]]•[[ASCO]]</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;">[[联合免疫检查点抑制剂]]•[[克服EGFR-TKI耐药]]•[[PROTAC-mTOR降解剂]]•[[高血糖预测模型]]</td>
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