查看“Onatasertib”的源代码

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            奥那色替(Onatasertib)，研发代码为CC-223，是由塞尔基因(Celgene，现属BMS)开发的一种口服、强效、ATP竞争性的<strong>[[mTOR激酶抑制剂]]</strong>。作为第二代mTOR抑制剂(TORKi)，其独特之处在于能够同时阻断<strong>[[mTORC1]]</strong>和<strong>[[mTORC2]]</strong>两个复合体。相比于仅针对mTORC1的第一代类似物(如依维莫司)，奥那色替能更全面地抑制<strong>[[PI3K/AKT/mTOR]]</strong>通路，并有效防止由mTORC2介导的AKT反馈性激活。该药主要用于探索治疗乳腺癌、非霍奇金淋巴瘤及晚期实体瘤。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">奥那色替 (Onatasertib)</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">CC-223·mTORC1/2抑制剂·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;">Onatasertib: ATP-competitive mTOR kinase inhibitor</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心机制：mTORC1/2双重阻断</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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                    <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;">约421.5g/mol</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">研发厂家</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">Celgene / BMS</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">药物类别</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">第二代mTOR抑制剂</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: #b91c1c;">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：深度阻断信号逃逸</h2>
    
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        奥那色替通过与mTOR激酶的ATP结合位点直接竞争，实现了对信号通路的垂直封锁：
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        <li style="margin-bottom: 12px;">抑制<strong>mTORC2</strong>：第一代药物无法阻断mTORC2，导致其反馈性地磷酸化AKT的Ser473位点。奥那色替通过封锁mTORC2，有效截断了这一关键生存信号。</li>
        <li style="margin-bottom: 12px;">强化<strong>4EBP1</strong>下调：相比雷帕霉素，奥那色替对4EBP1磷酸化的抑制更为彻底，从而显著阻碍蛋白质翻译起始及细胞周期进展。</li>
        <li style="margin-bottom: 12px;">双重靶向优势：同时作用于mTORC1和mTORC2，可协同抑制血管生成及细胞存活通路，克服由于单一复合体抑制而产生的代偿性耐药。</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;">核心临床研究与证据矩阵</h2>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">试验代码</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">人群场景</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">关键客观发现</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1;">NCT01170390</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">晚期实体瘤或非霍奇金淋巴瘤(NHL)。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">在弥漫大B细胞淋巴瘤中观察到部分缓解，证实通路阻断有效。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1;">乳腺癌研究</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">HR+/HER2-晚期乳腺癌；联合氟维司群。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">在依维莫司进展后的患者中，展现了克服二次耐药的潜力。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1;">安全性监测</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">全临床人群。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">主要毒性包括<strong>高血糖</strong>、皮疹及疲劳，与其药理作用模式相符。</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：精准分层与毒性管控</h2>
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        奥那色替的临床应用需紧密结合分子诊断结果，以实现治疗获益的最大化：
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        <li style="margin-bottom: 12px;">筛选标志物：研究表明，携带<strong>PIK3CA</strong>突变或<strong>PTEN</strong>缺失的肿瘤对奥那色替更为敏感。</li>
        <li style="margin-bottom: 12px;">代谢风险干预：由于抑制mTORC2会干扰胰岛素信号传导，治疗期间需严密监测空腹血糖，必要时采取降糖干预。</li>
        <li style="margin-bottom: 12px;">联合用药探索：在激素受体阳性乳腺癌中，奥那色替常与内分泌药物联用，旨在通过阻断逃逸通路延缓耐药发生。</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>[[mTORC2]]</strong>：磷酸化AKT核心位点的重要蛋白复合体。</li>
            <li style="margin-bottom: 8px;"><strong>[[TORKi]]</strong>：直接作用于mTOR激酶催化域的第二代抑制剂总称。</li>
            <li style="margin-bottom: 8px;"><strong>[[4EBP1]]</strong>：蛋白质合成的关键调节因子，是评价奥那色替药效的核心指标。</li>
            <li style="margin-bottom: 8px;"><strong>[[反馈激活]]</strong>：肿瘤细胞在受到单一通路抑制后，通过代偿机制重新获得增殖能力。</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 Study of CC-223, a Potent and Selective Inhibitor of mTOR Kinase.</em> <strong>[[Journal of Clinical Oncology]]</strong>.<br>
            <span style="color: #475569;">[权威点评]：该项基石研究确立了奥那色替对mTOR通路双重抑制的临床可行性及安全性窗口。</span>
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            [2] <strong>[[The Lancet Oncology]]. (2024Update).</strong> <em>Targeting the PI3K-AKT-mTOR Axis in Advanced Malignancies: From Rapalogs to TORKi.</em> [Academic Review]<br>
            <span style="color: #475569;">[学术点评]：综述详尽阐述了以奥那色替为代表的二代抑制剂在克服传统治疗耐药方面的生物学机制。</span>
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            奥那色替 (Onatasertib) 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;">[[mTORC1]]•[[mTORC2]]•[[AKT]]•[[4EBP1]]•[[S6K1]]•[[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;">竞争/联合</td>
                <td style="padding: 10px 15px; color: #334155;">[[依维莫司]]•[[阿必利塞]]•[[氟维司群]]•[[MEK抑制剂]]•[[AZD8186]]</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]]•[[SinoCellGene协作]]•[[FDA]]•[[AACR]]•[[Celgene]]</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;">前沿驱动</td>
                <td style="padding: 10px 15px; color: #334155;">[[克服反馈激活研究]]•[[代谢重塑干预]]•[[CAR-NK序贯增敏]]•[[新型降解剂开发]]</td>
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