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SHP2 - 版本历史
2026-04-19T05:47:12Z
本wiki的该页面的版本历史
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https://www.yiliao.com/index.php?title=SHP2&diff=316113&oldid=prev
2026年1月28日 (三) 20:44 77921020
2026-01-28T20:44:07Z
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<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">←上一版本</td>
<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">2026年1月28日 (三) 20:44的版本</td>
</tr><tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l3" >第3行：</td>
<td colspan="2" class="diff-lineno">第3行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <div style="margin-bottom: 30px; border-bottom: 1.2px solid #e2e8f0; padding-bottom: 25px;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <div style="margin-bottom: 30px; border-bottom: 1.2px solid #e2e8f0; padding-bottom: 25px;"></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;"></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <strong>SHP2</strong>（Src homology region 2 domain-containing phosphatase-2）是由 <strong><i>PTPN11</i></strong> <del class="diffchange diffchange-inline">基因编码的非受体型蛋白酪氨酸磷酸酶。与大多数抑制信号的磷酸酶不同，SHP2 </del>在肿瘤生物学中扮演着罕见的<strong>致癌性磷酸酶</strong>（Oncogenic <del class="diffchange diffchange-inline">Phosphatase）角色。它是连接上游受体酪氨酸激酶（</del><strong>[[RTK]]</strong>）与下游 <strong>[[RAS]]/<del class="diffchange diffchange-inline">MAPK</del></strong> <del class="diffchange diffchange-inline">通路的关键“中继站”或“转接头”。在靶向治疗（如针对 </del>[[KRAS G12C]] 或 EGFR 的抑制）中，肿瘤细胞常通过激活 SHP2 来介导<strong>适应性耐药</strong>（Adaptive Resistance）。因此，SHP2 抑制剂被视为克服多种靶向药耐药的“万能搭档”。</div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <strong>SHP2</strong>（Src homology region 2 domain-containing phosphatase-2）是由 <strong><i><ins class="diffchange diffchange-inline">[[</ins>PTPN11<ins class="diffchange diffchange-inline">]]</ins></i></strong> <ins class="diffchange diffchange-inline">基因编码的非受体型[[蛋白酪氨酸磷酸酶]]。与大多数抑制信号的磷酸酶不同，SHP2 </ins>在肿瘤生物学中扮演着罕见的<strong>致癌性磷酸酶</strong>（Oncogenic <ins class="diffchange diffchange-inline">Phosphatase）角色。它是连接上游[[受体酪氨酸激酶]]（</ins><strong>[[RTK]]</strong>）与下游 <strong>[[RAS]]/<ins class="diffchange diffchange-inline">[[MAPK通路]]</ins></strong> <ins class="diffchange diffchange-inline">的关键“中继站”或“转接头”。在[[靶向治疗]]（如针对 </ins>[[KRAS G12C]] 或 <ins class="diffchange diffchange-inline">[[</ins>EGFR<ins class="diffchange diffchange-inline">]] </ins>的抑制）中，肿瘤细胞常通过激活 SHP2 来介导<strong><ins class="diffchange diffchange-inline">[[</ins>适应性耐药<ins class="diffchange diffchange-inline">]]</ins></strong>（Adaptive Resistance）。因此，SHP2 抑制剂被视为克服多种靶向药耐药的“万能搭档”。</div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l30" >第30行：</td>
<td colspan="2" class="diff-lineno">第30行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">酶类别</th></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">酶类别</th></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">酪氨酸磷酸酶 (PTP)</td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;"><ins class="diffchange diffchange-inline">[[</ins>酪氨酸磷酸酶<ins class="diffchange diffchange-inline">]] </ins>(PTP)</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">结构域</th></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">结构域</th></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;"><del class="diffchange diffchange-inline">N-SH2, C-SH2</del>, PTP domain</td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;"><ins class="diffchange diffchange-inline">[[SH2结构域]]</ins>, PTP domain</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">功能角色</th></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">功能角色</th></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong><del class="diffchange diffchange-inline">RAS 通路正向调节</del></strong></td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong><ins class="diffchange diffchange-inline">[[RAS通路]]正向调节</ins></strong></td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l50" >第50行：</td>
<td colspan="2" class="diff-lineno">第50行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">主要应用</th></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">主要应用</th></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a;"><strong>克服耐药 (联合用药)</strong></td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a;"><strong>克服耐药 (<ins class="diffchange diffchange-inline">[[</ins>联合用药<ins class="diffchange diffchange-inline">]]</ins>)</strong></td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569;">代表药物</th></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569;">代表药物</th></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; color: #64748b;">TNO155, RMC-4630</td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; color: #64748b;"><ins class="diffchange diffchange-inline">[[</ins>TNO155<ins class="diffchange diffchange-inline">]]</ins>, RMC-4630</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </table></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </table></div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l63" >第63行：</td>
<td colspan="2" class="diff-lineno">第63行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin: 15px 0; text-align: justify;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin: 15px 0; text-align: justify;"></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> SHP2 <del class="diffchange diffchange-inline">的活性受极其精密的构象变化调控，这为药物设计提供了绝佳的变构位点：</del></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> SHP2 <ins class="diffchange diffchange-inline">的活性受极其精密的构象变化调控，这为药物设计提供了绝佳的[[变构位点]]：</ins></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <ul style="padding-left: 25px; color: #334155;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <ul style="padding-left: 25px; color: #334155;"></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>关 (Closed State)：</strong> 在基础状态下，SHP2 的 <strong>N-SH2 结构域</strong>像一个塞子一样，折叠并堵住了 <strong>PTP 催化结构域</strong><del class="diffchange diffchange-inline">的活性中心。这就是“自抑制”（Auto</del>-inhibition），此时酶没有活性。</li></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>关 (Closed State)：</strong> 在基础状态下，SHP2 的 <strong>N-SH2 结构域</strong>像一个塞子一样，折叠并堵住了 <strong>PTP 催化结构域</strong><ins class="diffchange diffchange-inline">的活性中心。这就是“[[自抑制]]”（Auto</ins>-inhibition），此时酶没有活性。</li></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>开 (Open State)：</strong> 当上游信号（如 EGFR <del class="diffchange diffchange-inline">激活）产生磷酸化酪氨酸（pY）肽段时，N</del>-SH2 结构域优先与这些 pY 肽段结合。这种结合导致构象改变，N-SH2 从催化域上“移开”，暴露出活性中心，SHP2 被激活。</li></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>开 (Open State)：</strong> 当上游信号（如 <ins class="diffchange diffchange-inline">[[</ins>EGFR<ins class="diffchange diffchange-inline">]] 激活）产生[[磷酸化酪氨酸]]（pY）肽段时，N</ins>-SH2 结构域优先与这些 pY 肽段结合。这种结合导致构象改变，N-SH2 从催化域上“移开”，暴露出活性中心，SHP2 被激活。</li></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>变构抑制剂：</strong> 目前的 SHP2 抑制剂（如 <del class="diffchange diffchange-inline">TNO155）是</del><strong>分子胶水</strong>。它们结合在 N-SH2, C-SH2 和 PTP 结构域的交界处，将 SHP2 强行<strong>锁死在“关”的状态</strong>，使其无法被上游信号激活。</li></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>变构抑制剂：</strong> 目前的 SHP2 抑制剂（如 <ins class="diffchange diffchange-inline">[[TNO155]]）是</ins><strong><ins class="diffchange diffchange-inline">[[</ins>分子胶水<ins class="diffchange diffchange-inline">]]</ins></strong>。它们结合在 N-SH2, C-SH2 和 PTP 结构域的交界处，将 SHP2 强行<strong>锁死在“关”的状态</strong>，使其无法被上游信号激活。</li></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </ul></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </ul></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l77" >第77行：</td>
<td colspan="2" class="diff-lineno">第77行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">适应性耐药的必经之路</h3></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">适应性耐药的必经之路</h3></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin-bottom: 0; text-align: justify; font-size: 0.95em; color: #334155;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin-bottom: 0; text-align: justify; font-size: 0.95em; color: #334155;"></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> 当我们使用 KRAS <del class="diffchange diffchange-inline">G12C 抑制剂（如</del>[[索托拉西布]]）或 <del class="diffchange diffchange-inline">MEK 抑制剂时，肿瘤细胞会感知到下游 </del>ERK <del class="diffchange diffchange-inline">信号的减弱，从而解除负反馈抑制（Feedback </del>Relief）。</div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> 当我们使用 <ins class="diffchange diffchange-inline">[[</ins>KRAS <ins class="diffchange diffchange-inline">G12C抑制剂]]（如</ins>[[索托拉西布]]）或 <ins class="diffchange diffchange-inline">[[MEK抑制剂]] 时，肿瘤细胞会感知到下游 [[</ins>ERK<ins class="diffchange diffchange-inline">]] 信号的减弱，从而解除[[负反馈]]抑制（Feedback </ins>Relief）。</div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>后果：</strong> 细胞疯狂上调膜表面的各种 <del class="diffchange diffchange-inline">RTK（EGFR</del>, FGFR, HER2, <del class="diffchange diffchange-inline">MET）。</del></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>后果：</strong> 细胞疯狂上调膜表面的各种 <ins class="diffchange diffchange-inline">[[RTK]]（[[EGFR]]</ins>, <ins class="diffchange diffchange-inline">[[</ins>FGFR<ins class="diffchange diffchange-inline">]]</ins>, <ins class="diffchange diffchange-inline">[[</ins>HER2<ins class="diffchange diffchange-inline">]]</ins>, <ins class="diffchange diffchange-inline">[[MET]]）。</ins></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>SHP2 的作用：</strong> 无论上调的是哪种 RTK，它们几乎都需要通过 SHP2 才能将信号传导给 <del class="diffchange diffchange-inline">RAS（特别是野生型 </del>RAS）。SHP2 就像一个<strong>信号漏斗</strong>，汇聚了所有的上游逃逸信号。</div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>SHP2 的作用：</strong> 无论上调的是哪种 RTK，它们几乎都需要通过 SHP2 才能将信号传导给 <ins class="diffchange diffchange-inline">[[RAS]]（特别是野生型 </ins>RAS）。SHP2 就像一个<strong>信号漏斗</strong>，汇聚了所有的上游逃逸信号。</div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>策略：</strong> 抑制 SHP2，相当于卡住了这个漏斗的脖子，同时切断了多条旁路激活途径。</div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>策略：</strong> 抑制 SHP2，相当于卡住了这个漏斗的脖子，同时切断了多条旁路激活途径。</div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l86" >第86行：</td>
<td colspan="2" class="diff-lineno">第86行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <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;">双重身份：免疫检查点下游</h2></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <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;">双重身份：免疫检查点下游</h2></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin: 15px 0; text-align: justify;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin: 15px 0; text-align: justify;"></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> SHP2 不仅在肿瘤细胞内促癌，在免疫细胞中也是“帮凶”。它是 <strong>[[PD-1]]</strong> 下游的关键效应分子。当 PD-1 与 PD-L1 结合后，会招募 SHP2，进而去磷酸化 <del class="diffchange diffchange-inline">T 细胞受体（TCR）信号通路，抑制 </del>T 细胞杀伤力。</div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> SHP2 不仅在肿瘤细胞内促癌，在免疫细胞中也是“帮凶”。它是 <strong>[[PD-1]]</strong> 下游的关键效应分子。当 PD-1 与 <ins class="diffchange diffchange-inline">[[</ins>PD-L1<ins class="diffchange diffchange-inline">]] </ins>结合后，会招募 SHP2，进而去磷酸化 <ins class="diffchange diffchange-inline">[[T细胞受体]]（TCR）信号通路，抑制 </ins>T 细胞杀伤力。</div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>双重获益：</strong> 抑制 SHP2 既能直接抑制肿瘤生长（细胞自主性），又能解除 T 细胞抑制（非细胞自主性），具有类似于 PD-1 抗体的免疫激活作用。</div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <br><strong>双重获益：</strong> 抑制 SHP2 既能直接抑制肿瘤生长（细胞自主性），又能解除 T 细胞抑制（非细胞自主性），具有类似于 PD-1 抗体的免疫激活作用。</div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l101" >第101行：</td>
<td colspan="2" class="diff-lineno">第101行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[TNO155]]</td></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[TNO155]]</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">Novartis</td></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">Novartis</td></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">+ <strong>KRAS <del class="diffchange diffchange-inline">G12C抑制剂</del></strong> (<del class="diffchange diffchange-inline">Adagrasib</del>/<del class="diffchange diffchange-inline">Sotorasib</del>)<br>+ EGFR抑制剂 (Nazartinib)</td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">+ <strong><ins class="diffchange diffchange-inline">[[</ins>KRAS <ins class="diffchange diffchange-inline">G12C]]</ins></strong> (<ins class="diffchange diffchange-inline">[[阿达格拉西布]]</ins>/<ins class="diffchange diffchange-inline">索托拉西布</ins>)<br>+ EGFR抑制剂 (<ins class="diffchange diffchange-inline">[[</ins>Nazartinib<ins class="diffchange diffchange-inline">]]</ins>)</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">RMC-4630</td></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">RMC-4630</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">Revolution / Sanofi</td></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">Revolution / Sanofi</td></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">+ KRAS G12C抑制剂<br>+ MEK抑制剂 (Cobimetinib)</td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">+ KRAS G12C抑制剂<br>+ <ins class="diffchange diffchange-inline">[[</ins>MEK抑制剂<ins class="diffchange diffchange-inline">]] </ins>(Cobimetinib)</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">JAB-3312</td></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">JAB-3312</td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">加科思 (Jacobio)</td></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">加科思 (Jacobio)</td></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">+ Glecirasib (KRAS G12C)<br><del class="diffchange diffchange-inline">强调口服生物利用度。</del></td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 10px; border: 1px solid #cbd5e1;">+ <ins class="diffchange diffchange-inline">[[</ins>Glecirasib<ins class="diffchange diffchange-inline">]] </ins>(KRAS G12C)<br><ins class="diffchange diffchange-inline">强调口服[[生物利用度]]。</ins></td></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </table></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </table></div></td></tr>
</table>
77921020
https://www.yiliao.com/index.php?title=SHP2&diff=316111&oldid=prev
77921020：建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面
2026-01-28T20:32:54Z
<p>建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面</p>
<p><b>新页面</b></p><div><div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff; max-width: 1200px; margin: auto;"><br />
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<strong>SHP2</strong>（Src homology region 2 domain-containing phosphatase-2）是由 <strong><i>PTPN11</i></strong> 基因编码的非受体型蛋白酪氨酸磷酸酶。与大多数抑制信号的磷酸酶不同，SHP2 在肿瘤生物学中扮演着罕见的<strong>致癌性磷酸酶</strong>（Oncogenic Phosphatase）角色。它是连接上游受体酪氨酸激酶（<strong>[[RTK]]</strong>）与下游 <strong>[[RAS]]/MAPK</strong> 通路的关键“中继站”或“转接头”。在靶向治疗（如针对 [[KRAS G12C]] 或 EGFR 的抑制）中，肿瘤细胞常通过激活 SHP2 来介导<strong>适应性耐药</strong>（Adaptive Resistance）。因此，SHP2 抑制剂被视为克服多种靶向药耐药的“万能搭档”。<br />
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<div class="medical-infobox mw-collapsible mw-collapsed" style="width: 100%; max-width: 320px; margin: 0 auto 35px auto; border: 1.2px solid #bae6fd; border-radius: 12px; background-color: #ffffff; box-shadow: 0 8px 20px rgba(0,0,0,0.05); overflow: hidden;"><br />
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<div style="padding: 15px; color: #1e40af; background: linear-gradient(135deg, #e0f2fe 0%, #bae6fd 100%); text-align: center; cursor: pointer;"><br />
<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">SHP2</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Protein Tyrosine Phosphatase (点击展开)</div><br />
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<div style="padding: 25px; text-align: center; background-color: #f8fafc;"><br />
[Image:SHP2_auto_inhibition_closed_vs_open_structure]<br />
<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">构象开关：闭合(失活) vs 开放(激活)</div><br />
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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;">分子档案</th><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">编码基因</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;"><i>[[PTPN11]]</i></td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">酶类别</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">酪氨酸磷酸酶 (PTP)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">结构域</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">N-SH2, C-SH2, PTP domain</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">功能角色</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>RAS 通路正向调节</strong></td><br />
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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;">临床相关</th><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">遗传病</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[努南综合征]] (Noonan)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">主要应用</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a;"><strong>克服耐药 (联合用药)</strong></td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569;">代表药物</th><br />
<td style="padding: 6px 12px; color: #64748b;">TNO155, RMC-4630</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：精巧的“自抑制”开关</h2><br />
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<p style="margin: 15px 0; text-align: justify;"><br />
SHP2 的活性受极其精密的构象变化调控，这为药物设计提供了绝佳的变构位点：<br />
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<ul style="padding-left: 25px; color: #334155;"><br />
<li style="margin-bottom: 12px;"><strong>关 (Closed State)：</strong> 在基础状态下，SHP2 的 <strong>N-SH2 结构域</strong>像一个塞子一样，折叠并堵住了 <strong>PTP 催化结构域</strong>的活性中心。这就是“自抑制”（Auto-inhibition），此时酶没有活性。</li><br />
<li style="margin-bottom: 12px;"><strong>开 (Open State)：</strong> 当上游信号（如 EGFR 激活）产生磷酸化酪氨酸（pY）肽段时，N-SH2 结构域优先与这些 pY 肽段结合。这种结合导致构象改变，N-SH2 从催化域上“移开”，暴露出活性中心，SHP2 被激活。</li><br />
<li style="margin-bottom: 12px;"><strong>变构抑制剂：</strong> 目前的 SHP2 抑制剂（如 TNO155）是<strong>分子胶水</strong>。它们结合在 N-SH2, C-SH2 和 PTP 结构域的交界处，将 SHP2 强行<strong>锁死在“关”的状态</strong>，使其无法被上游信号激活。</li><br />
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<br />
<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;">耐药的“漏斗”：为何要抑制它？</h2><br />
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<div style="background-color: #f0f9ff; border-left: 5px solid #1e40af; padding: 15px 20px; margin: 20px 0; border-radius: 4px;"><br />
<h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">适应性耐药的必经之路</h3><br />
<p style="margin-bottom: 0; text-align: justify; font-size: 0.95em; color: #334155;"><br />
当我们使用 KRAS G12C 抑制剂（如[[索托拉西布]]）或 MEK 抑制剂时，肿瘤细胞会感知到下游 ERK 信号的减弱，从而解除负反馈抑制（Feedback Relief）。<br />
<br><strong>后果：</strong> 细胞疯狂上调膜表面的各种 RTK（EGFR, FGFR, HER2, MET）。<br />
<br><strong>SHP2 的作用：</strong> 无论上调的是哪种 RTK，它们几乎都需要通过 SHP2 才能将信号传导给 RAS（特别是野生型 RAS）。SHP2 就像一个<strong>信号漏斗</strong>，汇聚了所有的上游逃逸信号。<br />
<br><strong>策略：</strong> 抑制 SHP2，相当于卡住了这个漏斗的脖子，同时切断了多条旁路激活途径。<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;">双重身份：免疫检查点下游</h2><br />
<p style="margin: 15px 0; text-align: justify;"><br />
SHP2 不仅在肿瘤细胞内促癌，在免疫细胞中也是“帮凶”。它是 <strong>[[PD-1]]</strong> 下游的关键效应分子。当 PD-1 与 PD-L1 结合后，会招募 SHP2，进而去磷酸化 T 细胞受体（TCR）信号通路，抑制 T 细胞杀伤力。<br />
<br><strong>双重获益：</strong> 抑制 SHP2 既能直接抑制肿瘤生长（细胞自主性），又能解除 T 细胞抑制（非细胞自主性），具有类似于 PD-1 抗体的免疫激活作用。<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;">研发全景：为联合而生</h2><br />
<div style="overflow-x: auto; margin: 30px auto; max-width: 95%;"><br />
<table style="width: 100%; border-collapse: collapse; border: 1.2px solid #cbd5e1; font-size: 0.9em; text-align: left;"><br />
<tr style="background-color: #f8fafc; border-bottom: 2px solid #0f172a;"><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">药物代码</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">公司</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">主要联合策略</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[TNO155]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Novartis</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">+ <strong>KRAS G12C抑制剂</strong> (Adagrasib/Sotorasib)<br>+ EGFR抑制剂 (Nazartinib)</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">RMC-4630</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Revolution / Sanofi</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">+ KRAS G12C抑制剂<br>+ MEK抑制剂 (Cobimetinib)</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">JAB-3312</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">加科思 (Jacobio)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">+ Glecirasib (KRAS G12C)<br>强调口服生物利用度。</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>Chen YN, et al. (2016).</strong> <em>Allosteric inhibition of SHP2 promotes anticancer therapeutic efficacy.</em> <strong>[[Nature]]</strong>. <br><br />
<span style="color: #475569;">[点评]：诺华团队的奠基之作，发现了首个强效、高选择性的变构抑制剂 SHP099（TNO155的前体），证明了锁定“自抑制构象”的可行性。</span><br />
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[2] <strong>Mainardi S, et al. (2018).</strong> <em>SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo.</em> <strong>[[Nature Medicine]]</strong>. <br><br />
<span style="color: #475569;">[点评]：揭示了 SHP2 在 KRAS 突变肺癌中的关键作用，证明了抑制 SHP2 可以打破对 MEK 抑制剂的适应性耐药。</span><br />
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[3] <strong>Ruess DA, et al. (2018).</strong> <em>Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase.</em> <strong>[[Nature Medicine]]</strong>. <br><br />
<span style="color: #475569;">[点评]：与 Mainardi 的文章同期发表，进一步确认了 SHP2 是 KRAS 驱动癌症中的“阿喀琉斯之踵”，为联合用药奠定了基础。</span><br />
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SHP2 · 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;">上下游</td><br />
<td style="padding: 10px 15px; color: #334155;">[[RTK]] (EGFR/MET) &rarr; <strong>SHP2</strong> &rarr; [[SOS1]] &rarr; [[RAS]]</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;">联合策略</td><br />
<td style="padding: 10px 15px; color: #334155;">[[双重抑制]] • [[KRAS G12C]] • [[反馈性激活]]</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;">抑制机制</td><br />
<td style="padding: 10px 15px; color: #334155;">[[变构抑制]] • [[分子胶水]] • [[自抑制]]</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;">免疫相关</td><br />
<td style="padding: 10px 15px; color: #334155;">[[PD-1]] 下游 • [[T细胞耗竭]]</td><br />
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