查看“Tomivosertib”的源代码

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            <strong>Tomivosertib</strong>（研发代号：<strong>eFT508</strong>）是由 eFFECTOR Therapeutics 开发的一款高效、高选择性、口服 <strong>[[Mnk1]]/[[Mnk2]]</strong>（MAPK Interacting Kinases）抑制剂。该药物通过阻断 Mnk 对真核翻译起始因子 <strong>[[eIF4E]]</strong> (Ser209) 的磷酸化，特异性抑制一系列关键致癌因子（如 Cyclin D1, c-Myc）和免疫检查点蛋白（如 <strong>[[PD-L1]]</strong>）的 mRNA 翻译。与阻断全局蛋白合成的 mTOR 抑制剂不同，Tomivosertib 仅重塑“致癌翻译程序”，对正常细胞的基础代谢影响极小。目前，其临床开发重点在于与免疫检查点抑制剂（如 Pembrolizumab）联用，以通过下调 PD-L1 表达来增强抗肿瘤免疫反应。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Tomivosertib</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">eFT508 / Mnk1/2 Inhibitor (点击展开)</div>
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                [Image:Tomivosertib_chemical_structure_and_Mnk_binding]
                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">机制：立体选择性抑制 Mnk 激酶</div>
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            <table style="width: 100%; border-spacing: 0; border-collapse: collapse; font-size: 0.85em;">
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                    <th colspan="2" style="padding: 8px 12px; background-color: #e0f2fe; color: #1e40af; text-align: left; font-size: 0.9em; border-top: 1px solid #bae6fd;">药物化学参数</th>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">通用名</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">Tomivosertib</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">研发代号</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">eFT508</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">CAS 号</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1642878-37-8</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">479.52 g/mol</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">给药途径</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a;">口服 (Oral)</td>
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                    <th colspan="2" style="padding: 8px 12px; background-color: #e0f2fe; color: #1e40af; text-align: left; font-size: 0.9em; border-top: 1px solid #bae6fd;">药理学特征</th>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">核心靶点</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[Mnk1]] (MKNK1)<br>[[Mnk2]] (MKNK2)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">IC50</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">1-2 nM (高度亲和)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">直接效应</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">抑制 [[eIF4E]] 磷酸化</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">下游结果</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">下调 PD-L1, c-Myc, Cyclin D1</td>
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                    <th colspan="2" style="padding: 8px 12px; background-color: #e0f2fe; color: #1e40af; text-align: left; font-size: 0.9em; border-top: 1px solid #bae6fd;">临床开发状态</th>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">研发机构</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">eFFECTOR Therapeutics</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">最高阶段</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">Phase IIb</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">主要适应症</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[非小细胞肺癌]] (NSCLC)<br>[[乳腺癌]], 淋巴瘤</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569;">联合用药</th>
                    <td style="padding: 6px 12px; color: #16a34a;">[[Pembrolizumab]] (PD-1)<br>[[Paclitaxel]] (化疗)</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：精准的“翻译手术”</h2>
    
    <p style="margin: 15px 0; text-align: justify;">
        Tomivosertib 的作用机制代表了抗癌药物从“阻断信号”到“阻断执行”的转变：
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        <li style="margin-bottom: 12px;"><strong>靶点特异性：</strong> 
            <br>Tomivosertib 强效结合并抑制 Mnk1 和 Mnk2 的激酶活性。由于 Mnk 是 <strong>eIF4E</strong>（Ser209 位点）唯一的生理性激酶，该药物能完全阻断 eIF4E 的磷酸化。</li>
        <li style="margin-bottom: 12px;"><strong>选择性翻译抑制 (Selective Translation)：</strong> 
            <br>eIF4E 磷酸化对于大多数管家基因（Housekeeping genes）的翻译并非必需，但对于一类特定的<strong>“促癌 mRNA”</strong>至关重要。这类 mRNA（如 c-Myc, Mcl-1, VEGF）通常在 5' 非翻译区（5' UTR）具有复杂的二级结构或较长的序列。Tomivosertib 通过去磷酸化 eIF4E，特异性降低这类 mRNA 与核糖体的结合效率，从而在不杀死正常细胞的前提下“饿死”癌细胞。</li>
        <li style="margin-bottom: 12px;"><strong>免疫调节 (Immunomodulation)：</strong> 
            <br>研究发现，免疫检查点蛋白 <strong>[[PD-L1]]</strong> 的 mRNA 也是高度依赖 Mnk-eIF4E 通路进行翻译的。Tomivosertib 能显著下调肿瘤细胞表面的 PD-L1 蛋白水平，从而解除其对 T 细胞的抑制。</li>
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    [Image:Mnk_inhibitor_translation_control_mechanism]

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        <h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">Why it is safe?</h3>
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            传统的翻译抑制剂（如 mTOR 抑制剂）往往因为阻断了所有蛋白合成而产生严重的毒性。然而，基因敲除小鼠模型显示，<strong>缺失 Mnk1 和 Mnk2 的小鼠发育完全正常</strong>，且无明显的生理缺陷。这表明 eIF4E 的磷酸化是“锦上添花”而非“雪中送炭”的过程。这赋予了 Tomivosertib 极佳的治疗窗口（Therapeutic Window）和安全性。
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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;">临床版图与挑战</h2>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">试验方向</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">联合策略</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">临床逻辑</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">非小细胞肺癌 (NSCLC)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">+ [[Pembrolizumab]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">利用 Tomivosertib 下调 PD-L1，克服 PD-1 抗体的继发性耐药。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">乳腺癌 (HR+)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">+ [[Paclitaxel]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">抑制 Cyclin D1 和 Mcl-1，增强紫杉醇的细胞杀伤力并延缓耐药。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">淋巴瘤 (DLBCL)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">单药或联合</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">针对依赖 Myc 和 Bcl-2 家族蛋白的高侵袭性淋巴瘤。</td>
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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 [Academic Review]</span>
        
        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [1] <strong>Reich SH, et al. (2018).</strong> <em>Structure-based design of eFT508, a potent and selective inhibitor of MNK1 and MNK2.</em> <strong>[[Journal of Medicinal Chemistry]]</strong>. <br>
            <span style="color: #475569;">[点评]：药物化学领域的奠基之作，详细描述了 Tomivosertib 的分子设计过程、晶体结构结合模式及高度选择性。</span>
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        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [2] <strong>Xu Y, et al. (2019).</strong> <em>Translation control of the immune checkpoint PD-L1 via eIF4E phosphorylation.</em> <strong>[[Nature Medicine]]</strong>. <br>
            <span style="color: #475569;">[点评]：里程碑式研究，首次揭示了 eIF4E 磷酸化调控 PD-L1 翻译的机制，为 Tomivosertib 联合免疫治疗提供了坚实的理论基础。</span>
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        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [3] <strong>Ueda T, et al. (2004).</strong> <em>Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth.</em> <strong>[[Molecular and Cellular Biology]]</strong>. <br>
            <span style="color: #475569;">[点评]：利用基因敲除小鼠证明了 Mnk 的功能冗余性和非必需性，确立了该靶点的安全性。</span>
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            Tomivosertib · 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;">分子靶点</td>
                <td style="padding: 10px 15px; color: #334155;">[[Mnk1]] (诱导型) • [[Mnk2]] (组成型) • [[eIF4E]]</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;">翻译底物</td>
                <td style="padding: 10px 15px; color: #334155;">[[PD-L1]] (免疫) • [[c-Myc]] (增殖) • [[Mcl-1]] (抗凋亡)</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;">联合策略</td>
                <td style="padding: 10px 15px; color: #334155;">[[免疫检查点抑制剂]] (ICI) • [[紫杉醇]] • [[KRAS抑制剂]]</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;">竞争药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[Cercosporamide]] • [[Merestinib]] (多靶点)</td>
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