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<strong>HRS-4642</strong> 是由江苏恒瑞医药（Hengrui Medicine）自主研发的一款高选择性、<strong>非共价</strong>（Non-covalent）的 <strong>KRAS G12D</strong> 抑制剂。KRAS G12D 是胰腺癌、结直肠癌和部分肺癌中最常见的 KRAS 突变亚型。HRS-4642 采用了独特的<strong>脂质体</strong>（Liposome）剂型设计，以解决药物溶解度和体内分布问题，是全球范围内首个进入临床阶段的 KRAS G12D 抑制剂。目前，该药物正在全球多地开展针对实体瘤的 I/II 期临床试验，与美国的 MRTX1133 和 RMC-9805 等药物展开激烈的同类最佳（Best-in-Class）竞争。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">HRS-4642</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">KRAS G12D Inhibitor (点击展开)</div><br />
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[[Image:HRS-4642_structure_concept.jpg|100px|脂质体包裹的小分子抑制剂示意图]]<br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">研发代号：HRS-4642</div><br />
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<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[恒瑞医药]] (Hengrui)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">核心靶点</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[KRAS G12D]]</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">头号竞品</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">[[MRTX1133]] (Mirati/BMS)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">其他竞品</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[RMC-9805]], [[ASP3082]]</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">药物剂型</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[脂质体]]注射液</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">给药方式</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">静脉注射 (IV)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">特殊AE</th><br />
<td style="padding: 6px 12px; color: #b91c1c;">[[高脂血症]] (载体相关)</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：攻克“最难突变”</h2><br />
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KRAS G12D 是 KRAS 家族中突变频率最高的亚型（约占所有 KRAS 突变的 40%），但药物开发难度远高于 G12C。HRS-4642 的机制创新点在于：<br />
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<li style="margin-bottom: 12px;"><strong>非共价结合 (Non-covalent Binding)：</strong> <br />
<br>G12D 突变将甘氨酸变为<strong>天冬氨酸</strong>（Asp），缺乏半胱氨酸的巯基，无法像 Sotorasib 那样形成共价键。HRS-4642 通过强效的非共价相互作用，占据 KRAS 蛋白的变构口袋，将其锁定在非活性的 GDP 结合状态，从而阻断下游 MAPK/ERK 通路。</li><br />
<li style="margin-bottom: 12px;"><strong>脂质体递送 (Liposomal Delivery)：</strong> <br />
<br>为了提高药物的溶解度、稳定性和在肿瘤组织的富集（EPR效应），HRS-4642 被封装在脂质体中。这种特殊的剂型使其在药代动力学上表现出长半衰期，但也带来了特定的不良反应（如高脂血症）。</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;">全球竞品格局：G12D 的争夺战</h2><br />
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<h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">差异化竞争</h3><br />
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G12D 抑制剂的研发主要分为三大路线：非共价小分子、PROTAC 降解剂和泛 RAS 抑制剂。HRS-4642 属于<strong>非共价小分子</strong>路线，其主要优势在于研发进度（全球首个入组）。<br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 20%;">药物名称</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">研发企业</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">技术路线</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">给药方式</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">HRS-4642</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">恒瑞医药 (中国)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">脂质体、非共价</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">静脉注射 (IV)</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600; background-color: #fee2e2;">MRTX1133</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2;">Mirati / BMS</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2;">长效、非共价</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2;">口服 (PO)</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">RMC-9805</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Revolution Med</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">RAS(ON) G12D 选择性</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">口服 (PO)</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">ASP3082</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Astellas</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">PROTAC 蛋白降解剂</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">静脉注射 (IV)</td><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 [Academic Review]</span><br />
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[1] <strong>Zhou C, et al. (2023).</strong> <em>First-in-human phase 1 study of HRS-4642, a KRAS G12D inhibitor, in patients with advanced solid tumors harboring KRAS G12D mutation.</em> <strong>[[ESMO Asia Congress 2023]]</strong>. <br><br />
<span style="color: #475569;">[点评]：首次在国际大会上披露了 HRS-4642 的人体临床数据，证实了其安全性和初步疗效，确立了其全球首发的地位。</span><br />
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[2] <strong>Wang X, et al. (2022).</strong> <em>Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor.</em> <strong>[[Journal of Medicinal Chemistry]]</strong>. <br><br />
<span style="color: #475569;">[点评]：详细阐述了最强竞品 MRTX1133 的药物化学设计，该药物目前被视为 G12D 领域的标杆分子。</span><br />
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[3] <strong>Jiangsu HengRui Medicine Co., Ltd. (2024).</strong> <em>A Study of HRS-4642 in Patients With Advanced Solid Tumors (NCT06385678).</em> <strong>[[ClinicalTrials.gov]]</strong>. <br><br />
<span style="color: #475569;">[点评]：注册临床试验信息，展示了其最新的联合治疗策略（联合化疗、免疫治疗）布局。</span><br />
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HRS-4642 · 知识图谱<br />
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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;">核心靶点</td><br />
<td style="padding: 10px 15px; color: #334155;">[[KRAS G12D]] • [[RAS通路]] • [[非共价抑制]]</td><br />
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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;">竞品药物</td><br />
<td style="padding: 10px 15px; color: #334155;">[[MRTX1133]] • [[RMC-9805]] • [[ASP3082]] • [[RMC-6236]]</td><br />
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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;">核心适应症</td><br />
<td style="padding: 10px 15px; color: #334155;">[[胰腺癌]] (PDAC) • [[结直肠癌]] (CRC) • [[卵巢癌]]</td><br />
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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;">技术特点</td><br />
<td style="padding: 10px 15px; color: #334155;">[[脂质体药物]] • [[高脂血症]] (AE) • [[静脉给药]]</td><br />
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