{"id":45792,"date":"2025-01-02T05:10:39","date_gmt":"2025-01-02T05:10:39","guid":{"rendered":"https:\/\/zydq.1006ss.com\/?p=45792"},"modified":"2025-01-02T05:10:39","modified_gmt":"2025-01-02T05:10:39","slug":"%e3%80%90%e4%b8%87%e5%ad%97%e7%bb%bc%e8%bf%b0%e3%80%91protac%e6%8a%80%e6%9c%af%e7%89%b9%e7%82%b9%e3%80%81%e9%ab%98%e6%95%88protac%e8%ae%be%e8%ae%a1%e7%9a%84%e4%b8%80%e8%88%ac%e5%8e%9f%e7%90%86","status":"publish","type":"post","link":"http:\/\/zydq.1006ss.com\/?p=45792","title":{"rendered":"\u3010\u4e07\u5b57\u7efc\u8ff0\u3011PROTAC\u6280\u672f\u7279\u70b9\u3001\u9ad8\u6548PROTAC\u8bbe\u8ba1\u7684\u4e00\u822c\u539f\u7406\u3001\u53ca\u9762\u4e34\u7684\u6311\u6218\u548c\u5c40\u9650"},"content":{"rendered":"

\u8fd1\u5e74\u6765\uff0c\u86cb\u767d\u6c34\u89e3\u9776\u5411\u5d4c\u5408\u4f53\uff08PROTAC\uff09\u6280\u672f\u5df2\u6210\u4e3a\u4e00\u79cd\u65b0\u578b\u6cbb\u7597\u8303\u4f8b\u3002PROTAC \u662f\u5f02\u53cc\u529f\u80fd\u5206\u5b50\uff0c\u901a\u8fc7\u52ab\u6301\u6cdb\u7d20-\u86cb\u767d\u9176\u4f53\u7cfb\u7edf\u6765\u964d\u89e3\u9776\u86cb\u767d\u3002\u76ee\u524d\uff0c\u5927\u7ea6 20-25% \u7684\u86cb\u767d\u8d28\u9776\u70b9\u6b63\u5728\u7814\u7a76\u4e2d\uff0c\u5927\u591a\u6570\u5de5\u4f5c\u90fd\u96c6\u4e2d\u5728\u5b83\u4eec\u7684\u9176\u529f\u80fd\u4e0a\u3002\u4e0e\u5c0f\u5206\u5b50\u4e0d\u540c\uff0cPROTAC \u901a\u8fc7\u4e0e\u9776\u86cb\u767d\u7ed3\u5408\u5e76\u8bf1\u5bfc\u968f\u540e\u7684\u86cb\u767d\u9176\u4f53\u964d\u89e3\u6765\u6291\u5236\u9776\u86cb\u767d\u7684\u6574\u4e2a\u751f\u7269\u5b66\u529f\u80fd\u3002PROTAC \u5f25\u8865\u4e86\u4f20\u7edf\u5c0f\u5206\u5b50\u6291\u5236\u5242\u96be\u4ee5\u5904\u7406\u8f6c\u5f55\u56e0\u5b50\u3001\u6838\u86cb\u767d\u548c\u5176\u4ed6\u652f\u67b6\u86cb\u767d\u7684\u5c40\u9650\u6027\u3002\u76ee\u524d\uff0cPROTACs\u5df2\u6210\u529f\u964d\u89e3\u591a\u79cd\u86cb\u767d\uff0c\u5982BTK\u3001BRD4\u3001AR\u3001ER\u3001STAT3\u3001IRAK4\u3001tau\u7b49\u3002\u7136\u800c\uff0c\u54ea\u4e9b\u9776\u70b9\u9002\u5408PROTAC\u6280\u672f\u4ee5\u5b9e\u73b0\u6bd4\u5c0f\u5206\u5b50\u6291\u5236\u5242\u66f4\u597d\u7684\u6548\u76ca\u5c1a\u4e0d\u5b8c\u5168\u6e05\u695a\u3002\u5982\u4f55\u5408\u7406\u8bbe\u8ba1\u9ad8\u6548\u7684PROTACs\u5e76\u4f18\u5316\u5176\u53e3\u670d\u6709\u6548\uff0c\u7ed9\u7814\u7a76\u4eba\u5458\u5e26\u6765\u4e86\u5de8\u5927\u7684\u6311\u6218\u3002<\/p>\n

\u5728\u8fd9\u7bc7\u7efc\u8ff0\u4e2d\uff0c\u6211\u4eec\u603b\u7ed3\u4e86PROTAC\u6280\u672f\u7684\u7279\u70b9\uff0c\u8be6\u7ec6\u5206\u6790\u4e86\u8bbe\u8ba1\u9ad8\u6548PROTAC\u7684\u4e00\u822c\u539f\u7406\uff0c\u5e76\u8ba8\u8bba\u4e86\u9488\u5bf9\u4e0d\u540c\u86cb\u767d\u8d28\u7c7b\u522b\u7684PROTAC\u7684\u5178\u578b\u5e94\u7528\u3002\u6b64\u5916\uff0c\u8bc4\u4f30\u4e86PROTAC\u53ef\u80fd\u9762\u4e34\u7684\u6311\u6218\u548c\u5c40\u9650\u6027\u3002<\/p>\n

1. \u80cc\u666f\u4ecb\u7ecd<\/p>\n

<\/h2>\n

Sakamoto \u7b49\u4eba2001\u5e74\u9996\u5148\u62a5\u9053\u4e86\u86cb\u767d\u6c34\u89e3\u9776\u5411\u5d4c\u5408\u4f53 (PROTAC)\u3002PROTAC \u662f\u5f02\u53cc\u529f\u80fd\u5206\u5b50\uff0c\u5305\u542b\u4e09\u4e2a\u7ec4\u4ef6\uff1a\u76ee\u7684\u86cb\u767d (POI) \u7ed3\u5408\u90e8\u5206\u3001\u63a5\u5934\u548c E3 \u6cdb\u7d20\u8fde\u63a5\u9176\u7ed3\u5408\u90e8\u5206\uff08\u56fe 1a) \u3002PROTAC\u5206\u5b50\u53ef\u4ee5\u4e0eE3\u8fde\u63a5\u9176\u548c\u9776\u86cb\u767d\u7ed3\u5408\u5f62\u6210POI-PROTAC-E3\u8fde\u63a5\u9176\u4e09\u5143\u590d\u5408\u7269\u3002\u52ab\u6301\u6cdb\u7d20\u86cb\u767d\u9176\u7cfb\u7edf\uff08UPS\uff09\u968f\u540e\u5bfc\u81f4\u76ee\u6807\u86cb\u767d\u88ab\u591a\u6cdb\u7d20\u5316\uff0c\u7136\u540e\u86cb\u767d\u8d28\u88ab\u86cb\u767d\u9176\u4f53\u964d\u89e3\u3002PROTAC \u540c\u65f6\u62db\u52df E3 \u8fde\u63a5\u9176\u548c POI\uff0c\u4f7f POI \u548c E3 \u8fde\u63a5\u9176\u5728\u7a7a\u95f4\u4e0a\u63a5\u8fd1\u3002PROTAC \u6a21\u62df E3 \u8fde\u63a5\u9176\u5bf9\u5e95\u7269\u7684\u7279\u5f02\u6027\u8bc6\u522b\u5e76\u52ab\u6301\u7ec6\u80de\u5185\u86cb\u767d\u8d28\u7834\u574f\u673a\u5236\u4ee5\u4ece\u7ec6\u80de\u4e2d\u53bb\u9664 POIs\u3002<\/p>\n<\/p>\n

\u56fe 1. a.\u57fa\u4e8eUPS\u7684PROTAC\u673a\u5236\u3002UPS \u7531\u7528\u6cdb\u7d20\u4fee\u9970\u86cb\u767d\u8d28\u7684\u7279\u5b9a\u9176\uff08E1\u3001E2 \u548c E3\uff09\u548c\u964d\u89e3\u6cdb\u7d20\u6807\u7b7e\u86cb\u767d\u7684\u86cb\u767d\u9176\u4f53\u7ec4\u6210\u3002PROTAC \u5305\u542b POI \u914d\u4f53\u3001E3 \u914d\u4f53\u548c\u63a5\u5934\u3002E3-PROTAC-POI \u4e09\u5143\u590d\u5408\u7269\u8bf1\u5bfc POI \u7684\u591a\u6cdb\u7d20\u5316\u548c\u86cb\u767d\u9176\u4f53\u4ecb\u5bfc\u7684\u964d\u89e3\u3002b. PROTAC \u6280\u672f\u53d1\u5c55\u7684\u91cc\u7a0b\u7891<\/p>\n

\u73b0\u4ee3\u836f\u7269\u53d1\u73b0\u7684\u91cd\u70b9\u662f\u5bfb\u627e\u4e0e\u76ee\u6807\u86cb\u767d\u5177\u6709\u9ad8\u7ed3\u5408\u4eb2\u548c\u529b\u7684\u5c0f\u5206\u5b50\uff0c\u8fd9\u4e9b\u5c0f\u5206\u5b50\u901a\u8fc7\u5360\u636e\u9176\u6d3b\u6027\u4f4d\u70b9\u6765\u8c03\u8282\u86cb\u767d\u529f\u80fd\u3002\u7136\u800c\uff0c\u4e00\u4e9b\u86cb\u767d\u8d28\u7f3a\u4e4f\u53ef\u7ed3\u5408\u4f4d\u70b9\u6216\u9176\u6d3b\u6027\u4f4d\u70b9\uff0c\u5982\u8f6c\u5f55\u56e0\u5b50\u3001RAS\u5bb6\u65cf\u86cb\u767d\u3001\u652f\u67b6\u86cb\u767d\u548c\u8c03\u8282\u86cb\u767d\uff0c\u4f7f\u5f97\u5b83\u4eec\u5bf9\u4f20\u7edf\u5c0f\u5206\u5b50\u836f\u7269\u4e0d\u654f\u611f\u3002\u968f\u7740 PROTAC \u7684\u51fa\u73b0\uff0c\u65e0\u9700\u8003\u8651\u6d3b\u6027\u4f4d\u70b9\u7684\u5b58\u5728\u5373\u53ef\u964d\u89e3\u201c\u4e0d\u53ef\u6210\u836f\u7684\u86cb\u767d\u8d28\u201d\u3002PROTAC \u5177\u6709\u72ec\u7279\u7684\u4f18\u52bf\uff0c\u62d3\u5bbd\u4e86\u672a\u6765\u836f\u7269\u53d1\u73b0\u7684\u89c6\u91ce\u3002\u4e00\u7cfb\u5217\u7528\u4e8e\u964d\u89e3\u96c4\u6fc0\u7d20\u53d7\u4f53\uff08AR\uff09\u548c\u96cc\u6fc0\u7d20\u53d7\u4f53\uff08ER\uff09\u7684PROTACs\u836f\u7269\u5df2\u8fdb\u5165\u4e34\u5e8a\u8bd5\u9a8c\u3002\u5230\u76ee\u524d\u4e3a\u6b62\uff0cPROTAC \u5df2\u88ab\u8bc1\u660e\u53ef\u4ee5\u6709\u6548\u964d\u89e3\u591a\u79cd\u86cb\u767d\u8d28\uff0c\u4f8b\u5982\u4ee3\u8868\u6027\u7684 AR\u3001ER \u6838\u53d7\u4f53\u3001\u5404\u79cd\u6fc0\u9176\u3001\u8f6c\u5f55\u56e0\u5b50\u548c\u5f02\u5e38\u86cb\u767d\u8d28\u805a\u96c6\u4f53\u3002<\/p>\n

2001\u5e74\uff0c\u62a5\u9053\u4e86\u7b2c\u4e00\u4e2aPROTAC\uff0c\u5b83\u7531\u62db\u52df\u86cb\u6c28\u9178\u6c28\u57fa\u80bd\u91762\uff08MetAP-2\uff09\u7684\u8840\u7ba1\u751f\u6210\u6291\u5236\u5242\u5375\u9178\u7d20\u548c\u62db\u52dfE3\u6cdb\u7d20\u8fde\u63a5\u9176\u03b2-TRCP\u7684I\u043aB\u03b1\u78f7\u9178\u80bd\u7ec4\u6210\u3002F-box \u86cb\u767d \u03b2-\u8f6c\u5bfc\u86cb\u767d\u91cd\u590d\u5e8f\u5217\u86cb\u767d (\u03b2-TRCP) \u5df2\u88ab\u8bc1\u660e\u53ef\u4e0e I\u043aB\u03b1\uff08NF-\u043aB \u7684\u8d1f\u8c03\u8282\u56e0\u5b50\uff09\u7ed3\u5408(\u5373\u8fde\u63a5\u7684\u53cc\u529f\u80fd\u80bd\u6bb5)\u3002\u7814\u7a76\u8868\u660e\uff0c\u8be5PROTAC\u53ef\u4ee5\u5728\u4f53\u5916\u6709\u6548\u964d\u4f4eMetAP-2\u6c34\u5e73\u3002\u5728\u7ec6\u80de\u5916\u7814\u7a76\u663e\u793a\u51fa\u5e0c\u671b\u540e\uff0c\u8fd9\u9879\u5f00\u521b\u6027\u7684\u5de5\u4f5c\u5f97\u4ee5\u6301\u7eed\u4e0b\u53bb\u30022003\u5e74\uff0cPROTAC\u88ab\u5e94\u7528\u4e8e\u9776\u5411\u964d\u89e3ER\u548cAR\u53d7\u4f53\u3002I\u043aB\u03b1 \u78f7\u9178\u80bd\u5206\u522b\u4e0e\u96cc\u4e8c\u9187\u548c\u4e8c\u6c22\u777e\u916e (DHT) \u8fde\u63a5\uff0c\u4f7f\u5f97 PROTAC \u80fd\u591f\u6709\u6548\u964d\u89e3 Er\u03b1 \u548c AR\u30022004\u5e74\uff0c\u542b\u6709E3\u8fde\u63a5\u9176\u7ed3\u5408\u80bdALAPYIP\u6765\u62db\u52dfvon Hippel-Lindau (VHL)\uff0c\u5b83\u53ef\u4ee5\u8bf1\u5bfcAR\u548cFK506\u7ed3\u5408\u86cb\u767d12 (FKBP12)\u7684\u964d\u89e3\u3002\u867d\u7136\u57fa\u4e8e\u80bd\u7684PROTAC\u5177\u6709\u751f\u7269\u76f8\u5bb9\u6027\u9ad8\u3001\u4f53\u5185\u6bd2\u6027\u4f4e\u7684\u4f18\u70b9\uff0c\u4f46\u4e0d\u80fd\u5ffd\u89c6\u5927\u5206\u5b50\u91cf\u5e26\u6765\u7684\u6709\u9650\u7684\u7ec6\u80de\u901a\u900f\u6027\u548c\u5408\u6210\u95ee\u9898\u3002\u968f\u7740E3\u8fde\u63a5\u9176\u5c0f\u5206\u5b50\u914d\u4f53\u7684\u53d1\u5c55\uff0c\u5982MDM2\u3001cIAP\u3001VHL\u3001Cereblon\uff08CRBN\uff09\u3001DCAF11\u3001DCAF15 \u3001DCAF16\u3001KEAP1\u548c RNF114\uff0cPROTAC \u5feb\u901f\u8fdb\u5165\u5c0f\u5206\u5b50\u5316\u3002<\/p>\n

CRBN E3\u590d\u5408\u7269\u7684\u7814\u7a76\u57282010\u5e74\u53d6\u5f97\u4e86\u91cd\u5927\u7a81\u7834\u3002CRBN\u662fCUL4-RBX1-DDB1-CRBN\uff08CRL4 CRBN\uff09E3\u6cdb\u7d20\u8fde\u63a5\u9176\u7684\u5e95\u7269\u53d7\u4f53\u4e9a\u57fa\uff0c\u5df2\u88ab\u786e\u5b9a\u4e3a\u6c99\u5229\u5ea6\u80fa\u514d\u75ab\u8c03\u8282\u836f\u7269\u7684\u76f4\u63a5\u9776\u70b9\uff08 IMiD\uff09\u3002\u8fd9\u4e9bIMiD\u7ed3\u5408CRBN\u8fde\u63a5\u9176\uff0c\u4e3a\u5177\u6709\u950c\u6307\u7ed3\u6784\u57df\u7684\u591a\u4e2a\u8f6c\u5f55\u56e0\u5b50\uff08\u4f8b\u5982IKZF1\u548cIKZF3\uff09\u63d0\u4f9b\u7ed3\u5408\u4f4d\u70b9\uff0c\u5f62\u6210\u5176\u6297\u764c\u4f5c\u7528\u7684\u57fa\u7840\u3002\u5728\u8fc7\u53bb\u7684\u51e0\u5e74\u4e2d\uff0c\u6c99\u5229\u5ea6\u80fa\u53ca\u5176\u884d\u751f\u7269\u56e0\u5176\u6709\u6548\u7684POI\u964d\u89e3\u548c\u826f\u597d\u7684\u6210\u836f\u6027\u800c\u6210\u529f\u5e94\u7528\u4e8ePROTAC\u4e2d\uff0c\u7528\u4e8e\u591a\u79cd\u86cb\u767d\u8d28\u7c7b\u522b\u7684\u9776\u5411\u964d\u89e3\u3002ARV-825\uff08\u56fe 2a) \u662f\u7b2c\u4e00\u4e2a\u7ed3\u5408\u6cca\u9a6c\u5ea6\u80fa\u548c\u542b\u6eb4\u7ed3\u6784\u57df\u86cb\u767d 4 (BRD4) \u6291\u5236\u5242 OTX015 \u7684 PROTAC\uff08\u56fe 2b\uff09\u3002\u8be5PROTAC\u53ef\u4ee5\u6709\u6548\u964d\u89e3\u4f2f\u57fa\u7279\u6dcb\u5df4\u7624(BL)\u7ec6\u80de\u4e2d\u7684BRD4\u86cb\u767d\u3002<\/p>\n<\/p>\n

\u56fe2. \u9488\u5bf9\u4e0d\u540c\u86cb\u767d\u8d28\u7684\u4ee3\u8868\u6027 PROTAC<\/p>\n

2012\u5e74\uff0cCrews\u548cCiulli\u56e2\u961f\u9274\u5b9a\u4e86\u7b2c\u4e00\u4e2a\u5177\u6709\u5fae\u6469\u5c14\u89e3\u79bb\u5e38\u6570\u7684VHL\u5c0f\u5206\u5b50\u914d\u4f53\u3002\u4e3a\u4e86\u63d0\u9ad8\u7b2c\u4e00\u4ee3VHL\u914d\u4f53\u7684\u4eb2\u548c\u529b\u548c\u4eb2\u8102\u6027\uff0cGaldeano\u7b49\u4eba\u53d1\u73b0\u4e86VHL \u7684\u7b2c\u4e8c\u4ee3\u914d\u4f53\uff0cVH032 \u88ab\u786e\u5b9a\u4e3a\u5177\u6709\u7eb3\u6469\u5c14\u4eb2\u548c\u529b\u3002\u65b0\u578b VHL E3 \u914d\u4f53\u7684\u9274\u5b9a\u6807\u5fd7\u7740 PORTAC \u6280\u672f\u7684\u4e00\u4e2a\u91cc\u7a0b\u7891\uff08\u56fe 1b)\u3002\u8fd9\u4e9b\u65b0\u53d1\u73b0\u7684VHL \u914d\u4f53\u4e3a\u8bbe\u8ba1 VHL \u62db\u52df PROTAC \u5f00\u8f9f\u4e86\u65b0\u7684\u673a\u4f1a\u3002VH032\u4e0eVHL\u7684\u6676\u4f53\u7ed3\u6784\uff0c\u4e3a\u6784\u5efa\u7b2c\u4e00\u4e2aVHL\u62db\u52dfPROTAC MZ1\u63d0\u4f9b\u4e86\u7ed3\u6784\u7ec6\u8282\uff08\u56fe 2b)\u3002\u5316\u5408\u7269 MZ1 \u80fd\u591f\u6709\u6548\u4e14\u9009\u62e9\u6027\u5730\u53bb\u9664 BRD4\u3002\u540e\u6765\u63ed\u793a\u4e86BRD4-MZ1-VHL\u590d\u5408\u7269\u7684\u6676\u4f53\u7ed3\u6784\uff0c\u63ed\u793a\u4e86MZ1\u88ab\u201c\u5939\u5728\u201dBRD4\u548cE3\u8fde\u63a5\u9176\u4e4b\u95f4\uff0c\u5e76\u4e14BRD4-VHL\u7684\u65b0\u63a5\u89e6\u662f\u7531MZ1\u8bf1\u5bfc\u7684\u534f\u540c\u8bc6\u522b\u4ea7\u751f\u7684\uff0c\u53d1\u73b0PROTAC\u8bf1\u5bfc\u7684\u9759\u7535\u8868\u9762\u9776\u86cb\u767d\u548c E3 \u8fde\u63a5\u9176\u4e4b\u95f4\u7684\u76f8\u4e92\u4f5c\u7528\u5bf9\u4e8e\u7a33\u5b9a\u4e09\u5143\u590d\u5408\u7269\u975e\u5e38\u91cd\u8981\u3002\u4e0a\u8ff0\u7a81\u7834\u6027\u7814\u7a76\u4e3a\u540e\u6765\u57fa\u4e8eVHL\u7684PROTAC\u7814\u7a76\u5960\u5b9a\u4e86\u57fa\u7840\u3002\u8fc4\u4eca\u4e3a\u6b62\uff0c\u57fa\u4e8eVHL\u7684PROTAC\u5df2\u6210\u529f\u5e94\u7528\u4e8e\u5404\u79cd\u75be\u75c5\u76f8\u5173\u86cb\u767d\u7684\u964d\u89e3\uff0c\u4f8b\u5982BCR-ABL\u3001ALK\u548cFAK\u3002<\/p>\n

\u8d8a\u6765\u8d8a\u591a\u7684\u9776\u70b9\u88ab\u786e\u8ba4\u4e3a\u201cPROTACable\u201d\u57fa\u56e0\u7ec4\uff0c\u90e8\u5206PROTAC\u5206\u5b50\u5df2\u53d6\u5f97\u4e34\u5e8a\u6548\u76ca\u3002\u4f8b\u5982\uff0c\u5df2\u8fdb\u5165\u4e34\u5e8a\u8bd5\u9a8c\u7684PROTAC\u9776\u70b9\u5305\u62ecAR\u3001ER\u3001IRAK4\u3001STAT3\u3001BTK\u3001BRD9\u3001BCR-Xl\u7b49\u3002\u81f3\u5c11\u670920\u4e2aPROTAC\u8fdb\u5165\u4e34\u5e8a\u8bd5\u9a8c\u3002\u5176\u4e2d\uff0c\u6765\u81eaArvinas\u7684ARV-110\u548cARV-471\u662f\u4e34\u5e8a\u7814\u7a76\u6700\u5148\u8fdb\u7684PROTAC\u836f\u7269\u3002Arvinas\u3001C4 Therapeutics\u3001Kymera Therapeutics \u548c Captor Therapeutics \u662f PROTAC \u9886\u57df\u7684\u5148\u950b\u5236\u836f\u516c\u53f8\uff0c\u63a8\u52a8\u4e86 PROTAC \u7684\u4e34\u5e8a\u8f6c\u5316\u3002Arvinas \u81f4\u529b\u4e8e\u5c06\u5176\u4ee3\u8868\u6027\u7684 ARV-110 \u548c ARV-471 \u63a8\u5411\u5e02\u573a\u3002ARV-110\u548cARV-471\u7684\u65e9\u671f\u4e34\u5e8a\u6570\u636e\u663e\u793a\u51fa\u7406\u60f3\u7684\u5b89\u5168\u6027\u3001\u6709\u6548\u66b4\u9732\u548c\u5bf9\u60a3\u8005\u6709\u610f\u4e49\u7684\u4e34\u5e8a\u7597\u6548\uff0c\u8bc1\u660e\u4e86\u8be5\u65b9\u6cd5\u7684\u6cbb\u7597\u53ef\u884c\u6027\u3002\u7814\u7a76\u6570\u636e\u8868\u660e\uff0cARV-110 \u4f5c\u4e3a\u53e3\u670d\u751f\u7269\u53ef\u5229\u7528\u7684\u964d\u89e3\u5242\u662f\u5b89\u5168\u7684\u3002I \u671f\u8bd5\u9a8c\u8868\u660e\uff0c\u5728\u5177\u6709\u7279\u5b9a\u57fa\u56e0\u7a81\u53d8\u7684\u4eba\u7fa4\u4e2d\uff0cARV-110 \u5c06 40% \u7684 mCRPC \u60a3\u8005\u7684\u524d\u5217\u817a\u7279\u5f02\u6027\u6297\u539f (PSA) \u6c34\u5e73\u964d\u4f4e\u4e86 50% \u4ee5\u4e0a\u3002\u6b64\u5916\uff0c\u5728\u6700\u521d\u7684\u4e34\u5e8a\u7814\u7a76\u4e2d\uff0c\u4e00\u540d\u60a3\u8005\u7684\u6d3b\u68c0\u6570\u636e\u663e\u793aAR\u4e0b\u964d\u4e8670%~90%\u3002\u4e00\u9879\u9488\u5bf9\u5e73\u5747\u63a5\u53d75\u6b21\u8fde\u7eed\u6cbb\u7597\u7684ER+\u548cHER2-\u4e73\u817a\u764c\u60a3\u8005\u7684I\u671f\u4e34\u5e8a\u7814\u7a76\u8868\u660e\uff0cARV-471\u53ef\u4ee5\u663e\u7740\u964d\u4f4e\u60a3\u8005\u80bf\u7624\u7ec4\u7ec7\u4e2dER\u7684\u8868\u8fbe\u6c34\u5e73\uff0c\u5e73\u5747\u964d\u4f4eER\u6c34\u5e7362% \uff0c\u6700\u591a\u53ef\u8fbe90%\u3002\u6b64\u5916\uff0cARV-471\u7684I\u671f\u4e34\u5e8a\u6570\u636e\u8fd8\u663e\u793a\uff0c\u572830-700 mg\u7684\u6240\u6709\u5242\u91cf\u6c34\u5e73\u4e0b\u5747\u89c2\u5bdf\u5230\u9ad8\u6c34\u5e73\u7684ER\u964d\u89e3\uff0889%\uff09\uff0c\u4e14\u8010\u53d7\u6027\u826f\u597d\u3002<\/p>\n

\u6700\u5148\u8fdb\u7684PROTAC\u836f\u7269ARV-110\u548cARV-471\u7684\u4e34\u5e8a\u8bd5\u9a8c\u7ed3\u679c\u88ab\u8ba4\u4e3a\u662fPROTAC\u9886\u57df\u53d1\u5c55\u7684\u98ce\u5411\u6807\u3002\u4f5c\u4e3a\u4e00\u79cd\u65b0\u7684\u836f\u7269\u8303\u5f0f\uff0cPROTAC\u836f\u7269\u7684\u4e34\u5e8a\u8f6c\u5316\u4ecd\u5b58\u5728\u76f8\u5f53\u5927\u7684\u7591\u95ee\u3002PROTAC\u5982\u4f55\u5728\u4e0d\u6ee1\u8db3Lipinski\u4e94\u6cd5\u5219\u7684\u60c5\u51b5\u4e0b\u4fdd\u8bc1\u6cbb\u7597\u6548\u679c\uff0c\u4ee5\u53ca\u5982\u4f55\u7814\u7a76\u3001\u9610\u660e\u548c\u51cf\u5c11PROTAC\u836f\u7269\u5f02\u53cc\u529f\u80fd\u5206\u5b50\u5f62\u5f0f\u53ef\u80fd\u5f15\u8d77\u7684\u590d\u6742\u8131\u9776\u6548\u5e94\u548c\u526f\u4f5c\u7528\uff0c\u662f\u4e34\u5e8a\u8bd5\u9a8c\u4e2d\u4e0d\u53ef\u907f\u514d\u7684\u6311\u6218\u3002\u4f5c\u4e3a\u9996\u6279\u8fdb\u5165III\u671f\u4e34\u5e8a\u8bd5\u9a8c\u7684PROTAC\u836f\u7269\uff0cARV-471\u5728\u65e9\u671f\u8bd5\u9a8c\u4e2d\u5c31\u8868\u73b0\u51fa\u4e86\u5f3a\u52b2\u7684\u4e34\u5e8a\u8868\u73b0\u3002\u5982\u679c\u540e\u7eed\u4e34\u5e8a\u8bd5\u9a8c\u7ed3\u679c\u80fd\u591f\u8fbe\u5230\u9884\u671f\u76ee\u6807\uff0cPROTAC\u53ef\u80fd\u4f1a\u5728\u4e0d\u4e45\u7684\u5c06\u6765\u8fdb\u5165\u4e34\u5e8a\u4f7f\u7528\uff0c\u8fd9\u5c06\u4e3a\u9776\u5411\u86cb\u767d\u964d\u89e3\u836f\u7269\u7684\u7814\u53d1\u5e26\u6765\u5386\u53f2\u6027\u7a81\u7834\u3002<\/p>\n

\u5728\u8fd9\u7bc7\u7efc\u8ff0\u4e2d\uff0c\u5217\u51fa\u4e86\u8fc7\u53bb 5 \u5e74\u6765 PROTAC \u9996\u6b21\u5e94\u7528\u7684\u9776\u6807\u3002\u540c\u65f6\u7b80\u8981\u56de\u987e\u4e00\u4e0b PROTAC \u6280\u672f\u4e0e\u5176\u4ed6\u6280\u672f\u76f8\u6bd4\u7684\u4f18\u52bf\u3002\u7136\u540e\uff0c\u4f5c\u8005\u6982\u8ff0\u4e86 PROTAC \u5728\u9776\u5411\u591a\u79cd\u76f8\u5173\u86cb\u767d\uff08\u5c24\u5176\u662f\u4e34\u5e8a\u8bd5\u9a8c\u4e2d\u7684\u5206\u5b50\uff09\u65b9\u9762\u7684\u6700\u65b0\u8fdb\u5c55\u3002\u8fd8\u8ba8\u8bba\u5e76\u63a8\u8350\u4e86\u8bbe\u8ba1\u65b0 PROTAC \u5206\u5b50\u7684\u57fa\u672c\u8003\u8651\u56e0\u7d20\u3002\u8bd5\u56fe\u4e3a\u76f8\u5173\u9886\u57df\u7684\u4eba\u4eec\u8bbe\u8ba1\u6709\u6548\u7684PROTAC\u63d0\u4f9b\u6709\u4ef7\u503c\u7684\u53c2\u8003\u3002<\/p>\n

2.PROTAC \u7684\u4f18\u70b9<\/p>\n

<\/h3>\n

<\/h2>\n

\u591a\u6837\u5316\u7684\u65b0\u578b\u6cbb\u7597\u7b56\u7565\uff08\u4f8b\u5982\u5c0f\u5206\u5b50\u6291\u5236\u5242\u3001\u5355\u514b\u9686\u6297\u4f53\u548cRNA\u5e72\u6270\uff08RNAi\uff09\uff09\u5df2\u6210\u4e3a\u836f\u7269\u53d1\u73b0\u7684\u65e2\u5b9a\u8303\u4f8b\u3002\u5c0f\u5206\u5b50\u6291\u5236\u5242\u7684\u6d3b\u6027\u901a\u5e38\u53d6\u51b3\u4e8e\u5360\u636e\u9776\u6807\u7684\u6d3b\u6027\u53e3\u888b\uff0c\u4e0e\u5185\u6e90\u914d\u4f53\u7ade\u4e89\u4ee5\u6291\u5236\u9776\u86cb\u767d\u6216\u9176\u7684\u529f\u80fd\u3002\u5c0f\u5206\u5b50\u6291\u5236\u5242\u7684\u957f\u671f\u4e34\u5e8a\u5e94\u7528\u9762\u4e34\u8010\u836f\u6027\u548c\u8131\u9776\u6548\u5e94\u7684\u6311\u6218\u3002\u5355\u514b\u9686\u6297\u4f53\u836f\u7269\u901a\u8fc7\u963b\u65ad\u7ec6\u80de\u5916\u86cb\u767d\u8d28-\u86cb\u767d\u8d28\u6216\u86cb\u767d\u8d28-\u914d\u4f53\u76f8\u4e92\u4f5c\u7528\u6765\u8c03\u8282\u7ec6\u80de\u53cd\u5e94\u3002\u5355\u514b\u9686\u6297\u4f53\u836f\u7269\u7684\u4e3b\u8981\u4f18\u70b9\u5728\u4e8e\u5176\u4e0e\u9776\u86cb\u767d\u7684\u9ad8\u4eb2\u548c\u529b\uff0c\u4f46\u5176\u4e0d\u8db3\u4e4b\u5904\u5728\u4e8e\u7ec6\u80de\u6e17\u900f\u6027\u5dee\u3001\u53e3\u670d\u4e0d\u53ef\u7528\u4ee5\u53ca\u6210\u672c\u9ad8\u3002RNA \u5e72\u6270\u7528\u4e8e\u901a\u8fc7\u6572\u4f4e mRNA \u6765\u8bf1\u5bfc\u57fa\u56e0\u6c89\u9ed8\uff0c\u56e0\u4e3a RNAi \u7684\u50ac\u5316\u6027\u8d28\u80fd\u591f\u964d\u89e3\u591a\u4e2a mRNA \u8f6c\u5f55\u672c\u3002\u7136\u800c\uff0c\u8131\u9776\u6548\u5e94\u3001\u53e3\u670d\u751f\u7269\u5229\u7528\u5ea6\u5dee\u548c\u7ec4\u7ec7\u6e17\u900f\u6027\u4e0d\u7406\u60f3\u4f7f\u5f97\u836f\u7269\u9012\u9001\u7814\u7a76\u5177\u6709\u6311\u6218\u6027\u3002\u4f5c\u4e3a\u4e00\u79cd\u6709\u524d\u9014\u7684\u6cbb\u7597\u8303\u4f8b\uff0cPROTACs \u6bd4\u5c0f\u5206\u5b50\u6291\u5236\u5242\u3001\u5355\u514b\u9686\u6297\u4f53\u548c\u5176\u4ed6\u6cbb\u7597\u7b56\u7565\u5177\u6709\u72ec\u7279\u7684\u4f18\u52bf\uff08\u8868 3\uff09\u3002\u5f53\u76ee\u6807\u86cb\u767d\u88ab\u86cb\u767d\u9176\u4f53\u964d\u89e3\u65f6\uff0cPROTACs\u53ef\u4ee5\u4ece\u590d\u5408\u7269\u4e2d\u89e3\u79bb\u51fa\u6765\uff0c\u5e76\u7ee7\u7eed\u53d1\u6325\u964d\u89e3\u4f5c\u7528\uff08\u79f0\u4e3a\u201c\u4e8b\u4ef6\u9a71\u52a8\u201d\u673a\u5236\uff09\uff0c\u4ece\u800c\u4f7f\u4f4e\u66b4\u9732\u91cf\u53d1\u6325\u529f\u6548\u3002\u6b64\u5916\uff0cPROTAC \u5b8c\u5168\u5e9f\u9664\u4e86\u9776\u6807\u7684\u529f\u80fd\uff0c\u751a\u81f3 POI\/E3 \u4eb2\u548c\u529b\u8f83\u4f4e\u7684\u914d\u4f53\u4e5f\u53ef\u7528\u4e8e\u9776\u6807\u964d\u89e3\u3002\u5728\u672c\u8282\u4e2d\uff0c\u6211\u4eec\u5c06\u7b80\u8981\u6bd4\u8f83 PROTAC \u4e0e\u5176\u4ed6\u6cbb\u7597\u7b56\u7565\u3002<\/p>\n

\u88683 PROTAC \u4e0e\u5176\u4ed6\u6cbb\u7597\u7b56\u7565\u7684\u6bd4\u8f83<\/h3>\n<\/p>\n

2.1 \u964d\u89e3\u201c\u4e0d\u53ef\u6210\u836f\u201d\u7684\u86cb\u767d\u8d28<\/h3>\n

\u5c3d\u7ba1FDA\u5df2\u7ecf\u6279\u51c6\u4e86\u8fd1400\u79cd\u9488\u5bf9\u4eba\u7c7b\u86cb\u767d\u8d28\u7684\u836f\u7269\uff0c\u4f46\u4e0e\u75be\u75c5\u76f8\u5173\u7684\u86cb\u767d\u8d28\u7ea6\u67093000\u79cd\uff0c\u8fdc\u8fdc\u8d85\u51fa\u4e86\u6211\u4eec\u7684\u5904\u7406\u80fd\u529b\u3002\u7136\u800c\uff0c\u5b83\u4eec\u4e2d\u7684\u5927\u591a\u6570\u6ca1\u6709\u5408\u9002\u7684\u6cbb\u7597\u836f\u7269\uff0c\u56e0\u4e3a\u7f3a\u4e4f\u6240\u8c13\u7684\u53ef\u6210\u836f\u6df1\u6c9f\u548c\u6d3b\u6027\u53e3\u888b\u6765\u5360\u636e\u5c0f\u5206\u5b50\uff0c\u4f8b\u5982\u652f\u67b6\u86cb\u767d\u3001\u8f6c\u5f55\u56e0\u5b50\u548cRAt\u8089\u7624\uff08RAS\uff09\u86cb\u767d\uff0c\u957f\u671f\u4ee5\u6765\u88ab\u8ba4\u4e3a\u662f\u201c\u4e0d\u53ef\u6210\u836f\u201d\u7684\u86cb\u767d\u8d28\u3002\u56e0\u6b64\uff0c\u5c0f\u5206\u5b50\u5f88\u96be\u8c03\u63a7\u8fd9\u4e9b\u4e0d\u53ef\u6210\u836f\u7684\u86cb\u767d\u8d28\uff0c\u53ea\u80fd\u4f9d\u9760\u6301\u7eed\u5360\u636e\u9776\u86cb\u767d\u7684\u7ed3\u5408\u53e3\u888b\u6765\u53d1\u6325\u5176\u836f\u7406\u6d3b\u6027\uff08\u79f0\u4e3a\u201c\u5360\u636e\u9a71\u52a8\u201d\u673a\u5236\uff09\u3002\u5e78\u8fd0\u7684\u662f\uff0cPROTAC \u8bf1\u5bfc\u7684\u86cb\u767d\u8d28\u964d\u89e3\u6709\u53ef\u80fd\u89e3\u51b3\u8fd9\u4e9b\u95ee\u9898\u3002\u4e0e\u4f20\u7edf\u7684\u5c0f\u5206\u5b50\u6291\u5236\u5242\u4e0d\u540c\uff0cPROTAC\u4e0d\u9700\u8981\u5bf9\u914d\u4f53\u7684\u9ad8\u4eb2\u548c\u529b\u548c\u6301\u4e45\u7684\u5360\u636e\uff0c\u5373\u4f7f\u662f\u4f4e\u4eb2\u548c\u529b\u7684\u914d\u4f53\u4e5f\u53ef\u4ee5\u8bf1\u5bfc\u9776\u86cb\u767d\u7684\u6709\u6548\u964d\u89e3\u3002\u5bf9\u4e8e\u8fd9\u4e9b\u5177\u6709\u6311\u6218\u6027\u7684\u4e0d\u53ef\u6210\u836f\u9776\u70b9\uff0cPROTAC \u53ef\u4ee5\u5728\u4e0d\u5b58\u5728\u6d3b\u6027\u53e3\u888b\u7684\u60c5\u51b5\u4e0b\u4e0e\u9776\u86cb\u767d\u7ed3\u5408\uff0c\u4ece\u800c\u5bfc\u81f4\u86cb\u767d\u9176\u4f53\u4ecb\u5bfc\u7684\u964d\u89e3\u5e76\u5b8c\u5168\u6291\u5236\u9776\u86cb\u767d\u7684\u751f\u7269\u5b66\u529f\u80fd\u3002\u4f8b\u5982\uff0cRAS \u86cb\u767d\u662f\u80ba\u764c\u3001\u7ed3\u76f4\u80a0\u764c\u548c\u80f0\u817a\u764c\u4e2d\u6700\u5e38\u89c1\u7a81\u53d8\u7684\u764c\u86cb\u767d\u3002RAS \u86cb\u767d\u5305\u542b\u4e09\u79cd\u4e9a\u578b\uff1aKRAS\u3001NRAS \u548c HRAS\u3002\u5176\u4e2d\uff0cKRAS\u7a81\u53d8\u662f\u764c\u75c7\u7684\u81f4\u547d\u9a71\u52a8\u56e0\u7d20\u3002\u7531\u4e8e\u4e4b\u524d\u7f3a\u4e4f\u660e\u786e\u7684\u7ed3\u5408\u888b\uff0cKRAS \u591a\u5e74\u6765\u4e00\u76f4\u88ab\u89c6\u4e3a\u4e0d\u53ef\u6210\u836f\u7684\u86cb\u767d\u8d28\u3002\u7136\u800c\uff0cFDA \u5feb\u901f\u8ddf\u8e2a\u4e86\u4e24\u79cd\u5171\u4ef7\u6291\u5236\u5242\u7684\u6307\u5b9a\uff0c\u5373 AMGEN \u7684 sotorasib (AMG 510) \u548c Mirati Therapeutics \u7684 adagrasib (MRTX849)\uff08\u56fe 2c)\uff0c\u4e24\u8005\u5747\u5728\u4e34\u5e8a\u8bd5\u9a8c\u4e2d\u8bc1\u660e\u4e86\u5bf9 KRASG12C \u7684\u6709\u6548\u6291\u5236\u4f5c\u7528\u3002\u4e0d\u5e78\u7684\u662f\uff0c\u957f\u671f\u548c\u957f\u65f6\u95f4\u7684\u4f7f\u7528\u4e0d\u53ef\u907f\u514d\u5730\u5bfc\u81f4\u4eb2\u548c\u529b\u4e25\u91cd\u4e0b\u964d\u548c\u83b7\u5f97\u6027\u8010\u836f\u6027\u30022020 \u5e74\uff0c\u901a\u8fc7\u5c06 MRTX849 \u4e0e VHL \u914d\u4f53\u8fde\u63a5\uff0c\u8bbe\u8ba1\u5e76\u5408\u6210\u4e86\u4e00\u7cfb\u5217 KRAS G12C PROTAC\u3002\u7ecf\u8fc7\u964d\u89e3\u6d3b\u6027\u7b5b\u9009\u540e\uff0c\u4ed6\u4eec\u786e\u5b9a\u4e86\u4e00\u79cd\u6700\u6709\u6548\u7684 PROTAC\uff0c\u5b83\u53ef\u4ee5\u5feb\u901f\u8bf1\u5bfc KRAS G12C\u86cb\u767d\u7684\u964d\u89e3\uff08DC 50 \u2009= 0.59 \u03bcM\uff0cNCI-H2030 \u7ec6\u80de\uff09\uff0c\u5e76\u4e14\u5728\u5176\u4ed6\u7ec6\u80de\u4e2d\u4e5f\u8868\u73b0\u51fa\u964d\u89e3\u6d3b\u6027\u3002<\/p>\n

2.2 \u63d0\u9ad8\u9009\u62e9\u6027\u548c\u7279\u5f02\u6027<\/h3>\n

\u836f\u7269\u5316\u5b66\u7814\u7a76\u4eba\u5458\u7684\u4e3b\u8981\u76ee\u6807\u662f\u53d1\u73b0\u5177\u6709\u9ad8\u9009\u62e9\u6027\u7684\u5206\u5b50\uff0c\u4ee5\u6700\u5927\u9650\u5ea6\u5730\u51cf\u5c11\u8131\u9776\u6548\u5e94\u5e26\u6765\u7684\u526f\u4f5c\u7528\u548c\u6bd2\u6027\u3002\u7136\u800c\uff0c\u7531\u4e8e\u540c\u4e00\u5bb6\u65cf\u7684\u86cb\u767d\u8d28\u4e4b\u95f4\u7684\u5dee\u5f02\u6709\u9650\uff0c\u56e0\u6b64\u5f88\u96be\u5b9e\u73b0\u3002\u76f8\u540c\u5bb6\u65cf\u86cb\u767d\u8d28\u4e4b\u95f4\u6c28\u57fa\u9178\u6b8b\u57fa\u7684\u7ec6\u5fae\u5dee\u5f02\u4e0d\u8db3\u4ee5\u4e3a\u5c0f\u5206\u5b50\u6291\u5236\u5242\u63d0\u4f9b\u8db3\u591f\u7684\u5206\u8fa8\u7387\u3002PROTAC\u72ec\u7279\u7684\u673a\u5236\u8d4b\u4e88\u5176\u53cc\u9009\u62e9\u6027\u5e95\u7269\u8bc6\u522b\u7684\u7279\u6027\u3002\u4e5f\u5c31\u662f\u8bf4\uff0c\u9664\u4e86\u76ee\u6807\u86cb\u767d\u914d\u4f53\u7684\u5e95\u7269\u9009\u62e9\u6027\u5916\uff0c\u964d\u89e3\u524d\u5f62\u6210\u7a33\u5b9a\u7684POI-PROTAC-E3\u4e09\u5143\u590d\u5408\u7269\u8fd8\u9700\u8981E3\u8fde\u63a5\u9176\u548c\u76ee\u6807\u86cb\u767d\u4e4b\u95f4\u9002\u5f53\u7684\u86cb\u767d\u8d28-\u86cb\u767d\u8d28\u76f8\u4e92\u4f5c\u7528\uff08PPI\uff09\u3002\u56e0\u6b64\uff0cE3\u8fde\u63a5\u9176\u4ece\u6574\u4e2a\u86cb\u767d\u8d28\u6c34\u5e73\u9009\u62e9\u6027\u8bc6\u522b\u9776\u86cb\u767d\u63d0\u9ad8\u4e86PROTAC\u7684\u9009\u62e9\u6027\u548c\u7279\u5f02\u6027\u3002\u6fc0\u9176\u4e9a\u578b\u9009\u62e9\u6027\u7684\u4e00\u4e2a\u5178\u578b\u4f8b\u5b50\u662f\u9488\u5bf9\u8840\u6e05\u548c\u7cd6\u76ae\u8d28\u6fc0\u7d20\u8bf1\u5bfc\u7684\u86cb\u767d\u6fc0\u9176 (SGK)\uff0cSGK \u5bb6\u65cf\u5305\u542b\u4e09\u79cd\u4e9a\u578b\uff1aSGK-1\u3001SGK-2 \u548c SGK-3\u3002\u636e\u62a5\u9053\uff0c\u7a81\u53d8\u7684PI3K\u53ef\u4ee5\u901a\u8fc7SGK3\u4f9d\u8d56\u6027\u673a\u5236\u8bf1\u5bfc\u80bf\u7624\u53d1\u751f\u3002\u4e00\u4e9b\u8bc1\u636e\u8868\u660e\uff0c\u5404\u79cd ATP \u7ade\u4e89\u6027\u6291\u5236\u5242\u5bf9\u6240\u6709 SGK \u5f02\u6784\u4f53\u7f3a\u4e4f\u9009\u62e9\u6027\uff0c\u56e0\u4e3a\u5b83\u4eec\u5bf9\u4e0d\u540c\u5f02\u6784\u4f53\u5177\u6709\u76f8\u4f3c\u7684\u4eb2\u548c\u529b \u3002\u7136\u800c\uff0c\u540c\u4e00\u5bb6\u65cf\u6210\u5458\u7684\u76f8\u4f3c\u50ac\u5316\u7ed3\u6784\u57df\u963b\u6b62\u4e86\u7814\u7a76\u4eba\u5458\u5f00\u53d1\u5f02\u6784\u4f53\u7279\u5f02\u6027\u6291\u5236\u5242\u3002\u4e3a\u4e86\u89e3\u51b3\u8fd9\u4e2a\u95ee\u9898\uff0c\u9ad8\u5ea6\u7279\u5f02\u6027\u7684SGK3-PROTAC1\uff08\u56fe 2d) \u5df2\u5f00\u53d1\u51fa\u6765\u3002\u8fd9\u79cdPROTAC\u662f\u57fa\u4e8e\u975eSGK3\u9009\u62e9\u6027\u6291\u5236\u5242308-R\u8bbe\u8ba1\u7684\uff0c\u7528\u4e8e\u7279\u5f02\u6027\u964d\u89e3SGK3\u3002\u5728\u4f4e\u5fae\u6469\u5c14\u6d53\u5ea6\u7684 SGK3-PROTAC1 \u4e0b\uff0c\u53ef\u4ee5\u663e\u7740\u964d\u4f4e\u7ec6\u80de\u5185 SGK3 \u6c34\u5e73\uff0c\u800c\u4e0d\u5f71\u54cd SGK1 \u548c SGK2\u3002\u53ef\u4ee5\u63a8\u6d4b\uff0cSGK3-PROTAC1\u7684\u9009\u62e9\u6027\u548c\u7279\u5f02\u6027\u6e90\u81eaSGK3-PROTAC1\u8bf1\u5bfc\u4e09\u5143\u590d\u5408\u7269\u5f62\u6210\u8fc7\u7a0b\u4e2dVHL\u5bf9SGK3\u7684\u9009\u62e9\u6027\u8bc6\u522b\u3002<\/p>\n

2.3 \u4f5c\u7528\u673a\u5236 (MOA)<\/h3>\n

\u4f20\u7edf\u7684\u5c0f\u5206\u5b50\u6291\u5236\u5242\u4ee5\u5242\u91cf\u4f9d\u8d56\u6027\u65b9\u5f0f\u53d1\u6325\u4f5c\u7528\uff0c\u901a\u8fc7\u6700\u5927\u5316\u836f\u7269\u53d7\u4f53\u5360\u636e\u6765\u8fbe\u5230\u4e34\u5e8a\u6548\u679c\u3002\u836f\u7269\u6d53\u5ea6\u8fc7\u9ad8\u4f1a\u5bfc\u81f4\u4e0d\u826f\u526f\u4f5c\u7528\u548c\u8131\u9776\u6548\u5e94\u3002PROTACs\u53ef\u4ee5\u542f\u52a8\u50ac\u5316\u9776\u86cb\u767d\u7684\u964d\u89e3\u5e76\u4ece\u86cb\u767d\u9176\u4f53\u4e2d\u9003\u9038\u3002\u7406\u8bba\u4e0a\uff0cPROTAC \u53ef\u4ee5\u4ee5\u66f4\u4f4e\u7684\u5242\u91cf\u3001\u66f4\u957f\u7684\u7ed9\u836f\u95f4\u9694\u8fdb\u884c\u9012\u9001\uff0c\u5e76\u4e14\u6bd4\u5c0f\u5206\u5b50\u6291\u5236\u5242\u5177\u6709\u66f4\u4f4e\u7684\u6bd2\u6027\uff0c\u56e0\u4e3a\u5b83\u4eec\u7684\u4f4e\u6d53\u5ea6\u8db3\u4ee5\u964d\u89e3\u86cb\u767d\u8d28\u5e76\u4e14\u4e0d\u53d7\u5e73\u8861\u5360\u7528\u7684\u9650\u5236\u3002\u7531\u4e8e\u5176\u50ac\u5316\u6027\u8d28\uff0c\u4f4e\u5242\u91cf\u7684 PROTAC \u53ef\u80fd\u4f1a\u964d\u4f4e\u53d1\u751f\u8131\u9776\u6548\u5e94\u7684\u53ef\u80fd\u6027\u3002<\/p>\n

2.4 \u6d88\u9664\u836f\u7269\u9776\u70b9\u7684\u79ef\u7d2f<\/h3>\n

\u5c0f\u5206\u5b50\u6291\u5236\u5242\u4e0e\u9776\u86cb\u767d\u7684\u7ed3\u5408\u5373\u4f7f\u5728\u76f8\u5bf9\u8f83\u77ed\u7684\u65f6\u95f4\u5185\u4e5f\u53ef\u4ee5\u589e\u52a0\u86cb\u767d\u8d28\u7684\u79ef\u7d2f\u3002\u53ef\u4ee5\u5f52\u56e0\u4e8e\u4e24\u4e2a\u539f\u56e0\uff1a1\uff09\u836f\u7269\u4e0e\u9776\u86cb\u767d\u7ed3\u5408\u53ef\u4ee5\u7a33\u5b9a\u86cb\u767d\u8d28\u7ed3\u6784\uff0c\u4ece\u800c\u5ef6\u957f\u5176\u534a\u8870\u671f\uff1b2)\u957f\u671f\u6291\u5236\u4f1a\u5bfc\u81f4\u5176\u4ee3\u507f\u6027\u8868\u8fbe\u4e0a\u8c03\u3002\u4e00\u822c\u6765\u8bf4\uff0c\u9776\u86cb\u767d\u7684\u79ef\u7d2f\u53ef\u80fd\u4e0d\u5229\u4e8e\u836f\u7269\u7684\u529f\u6548\u3002\u56e0\u6b64\uff0c\u5bf9\u4e8e\u8fd9\u4e9b\u5bf9\u6291\u5236\u5242\u4e0d\u654f\u611f\u7684\u86cb\u767d\u8d28\uff0c\u91c7\u53d6PROTAC\u4ecb\u5bfc\u7684\u86cb\u767d\u8d28\u964d\u89e3\u662f\u6781\u5176\u5408\u9002\u7684\u3002\u4f8b\u5982\uff0cBRD4\uff0c\u4f5c\u4e3a\u91cd\u8981\u7684\u6eb4\u7ed3\u6784\u57df\u548c\u672b\u7aef\u7ed3\u6784\u57df\uff08BET\uff09\u5bb6\u65cf\u6210\u5458\u4e4b\u4e00\u3002\u7814\u7a76\u4eba\u5458\u8bc1\u660e\uff0c\u9776\u5411 BRD4 \u662f\u6291\u5236 MYC \u9a71\u52a8\u7684\u764c\u75c7\u7684\u6709\u6548\u624b\u6bb5\u3002\u7136\u800c\uff0c\u5c0f\u5206\u5b50 BRD4 \u6291\u5236\u5242 JQ1\uff08\u56fe  2e) \u548c OTX015 \u5bfc\u81f4\u5927\u91cf\u86cb\u767d\u8d28\u79ef\u7d2f\uff0c\u9700\u8981\u9ad8\u6d53\u5ea6\u7684\u6291\u5236\u5242\u6765\u6291\u5236\u4e0b\u6e38 c-MYC\u30022015 \u5e74\uff0cLu \u7b49\u4eba\u901a\u8fc7\u52ab\u6301 CRBN E3 \u8fde\u63a5\u9176\u8bbe\u8ba1\u4e86\u4e00\u79cd\u6709\u6548\u7684 BRD4 PROTAC (ARV-825)\uff0c\u5b83\u8bf1\u5bfc\u6240\u6709 BL \u7ec6\u80de\u7cfb\u4e2d BRD4 \u86cb\u767d\u5feb\u901f\u6301\u7eed\u7684\u964d\u89e3\u3002\u8fd9\u51f8\u663e\u4e86 PROTAC \u76f8\u5bf9\u4e8e\u5c0f\u5206\u5b50\u6291\u5236\u5242\u7684\u4f18\u52bf\u3002<\/p>\n

2.5 \u5176\u4ed6\u7684\u4f18\u52bf<\/h3>\n

\u9664\u4e86\u4e0a\u8ff0\u51e0\u70b9\u4e4b\u5916\uff0cPROTAC \u8fd8\u5177\u6709\u5176\u4ed6\u4f18\u70b9\u3002\u83b7\u5f97\u6027\u8010\u836f\u7684\u53d1\u751f\u5f80\u5f80\u4e0e\u70b9\u7a81\u53d8\u5bc6\u5207\u76f8\u5173\uff0c\u70b9\u7a81\u53d8\u4f1a\u964d\u4f4e\u6291\u5236\u5242\u4e0e\u9776\u86cb\u767d\u7684\u4eb2\u548c\u529b\u3002PROTAC \u80fd\u591f\u901a\u8fc7\u5b8c\u5168\u6d88\u9664\u9776\u6807\u673a\u5236\u6765\u514b\u670d\u8010\u836f\u6027\u95ee\u9898\u3002\u6b64\u5916\uff0cPROTAC\u7684\u4e8b\u4ef6\u9a71\u52a8\u6a21\u578b\u4e0d\u9700\u8981\u9ad8\u836f\u7269\u66b4\u9732\u6765\u964d\u4f4e\u8131\u9776\u6548\u5e94\u7684\u98ce\u9669\u3002\u4e0e\u5176\u4ed6 DNA \u6c34\u5e73\u86cb\u767d\u8d28\u6572\u9664\u6280\u672f\u4e0d\u540c\uff0cPROTAC \u80fd\u591f\u5728\u7ffb\u8bd1\u540e\u6c34\u5e73\u5728\u4f53\u5185\u5feb\u901f\u964d\u89e3\u76ee\u6807\u86cb\u767d\u8d28\u3002\u5728\u9776\u5411\u86cb\u767d\u964d\u89e3\uff08TPD\uff09\u9886\u57df\uff0c\u9664\u4e86\u57fa\u4e8eUPS\u7684PROTAC\u4e4b\u5916\uff0c\u9776\u5411\u6eb6\u9176\u4f53\u7684\u5d4c\u5408\u4f53\uff08LYTAC\uff09\u3001\u9776\u5411\u81ea\u566c\u7684\u5d4c\u5408\u4f53\uff08AUTAC\uff09\u548c\u57fa\u4e8e\u6297\u4f53\u7684PROTAC\uff08AbTAC\uff09\u901a\u8fc7\u6eb6\u9176\u4f53\u964d\u89e3\u9776\u86cb\u767d\u3002PROTAC \u4e0d\u80fd\u964d\u89e3\u7ec6\u80de\u5916\u86cb\u767d\u548c\u819c\u86cb\u767d\u3002\u56e0\u6b64\uff0c\u6eb6\u9176\u4f53\u8bf1\u5bfc\u7684\u86cb\u767d\u8d28\u964d\u89e3\u53ef\u4ee5\u5f25\u8865 PROTAC \u7684\u7f3a\u4e4f\u3002LYTACs\u9996\u5148\u7531Banik\u7b49\u4eba\u63d0\u51fa\uff0c\u5e76\u7531\u7ed3\u5408\u6eb6\u9176\u4f53\u9776\u5411\u53d7\u4f53\uff08LTR\uff09\u7684\u914d\u4f53\u548c\u7ed3\u5408\u7ec6\u80de\u5916\u6216\u819c\u86cb\u767d\u7684\u914d\u4f53\u7ec4\u6210\u3002\u76ee\u524d\uff0c\u53ea\u6709\u805a\u4e1d\u6c28\u9178-O-\u7518\u9732\u7cd6-6-\u81a6\u9178\u916f\uff08M6Pn\uff09\u548cN-\u4e59\u9170\u534a\u4e73\u7cd6\u80fa\uff08Tri-GalNAC\uff09\u662f\u53ef\u7528\u7684LTR\u914d\u4f53\u3002LYTAC \u5df2\u88ab\u7528\u4e8e\u6210\u529f\u964d\u89e3\u8f7d\u8102\u86cb\u767d E4\u3001\u8868\u76ae\u751f\u957f\u56e0\u5b50\u53d7\u4f53 (EGFR)\u3001\u7a0b\u5e8f\u6027\u6b7b\u4ea1\u86cb\u767d\u914d\u4f53 1 (PD-L1) \u548c CD71 \u3002\u4f46\u7531\u4e8e\u5176\u5206\u5b50\u91cf\u5927\u3001\u7ec6\u80de\u901a\u900f\u6027\u5dee\u3001\u4f53\u5185\u53ef\u80fd\u51fa\u73b0\u514d\u75ab\u53cd\u5e94\uff0c\u8fd8\u9700\u8981\u8fdb\u4e00\u6b65\u7814\u7a76\u30022019 \u5e74\uff0c\u9ad8\u6865\u7b49\u4eba\u5f00\u53d1\u4e86\u57fa\u4e8e\u81ea\u566c\u8fc7\u7a0b\u7684 AUTAC\uff0c\u7528\u4e8e\u5185\u6e90\u6027\u86cb\u767d\u8d28\u7684\u964d\u89e3\u3002AUTAC \u662f\u4e00\u79cd\u53cc\u529f\u80fd\u5206\u5b50\uff0c\u5177\u6709\u8fde\u63a5 POI \u914d\u4f53\u548c\u81ea\u566c\u62db\u52df\u6807\u7b7e\u3002\u7136\u800c\uff0c\u7531\u4e8e\u7f3a\u4e4f\u6709\u6548\u7684\u81ea\u566c\u9014\u5f84\u62db\u52df\u914d\u4f53\uff0c\u76ee\u524d\u53d1\u8868\u7684 AUTAC \u6548\u7387\u4f4e\u4e0b\u3002\u81ea\u566c\u8fc7\u7a0b\u6781\u5176\u590d\u6742\uff0c\u53ef\u80fd\u5bf9\u81ea\u7136\u81ea\u566c\u4ea7\u751f\u5f71\u54cd\uff0cAUTACs\u7684\u4f5c\u7528\u673a\u5236\u5c1a\u4e0d\u6e05\u695a\uff0c\u56e0\u6b64\u9700\u8981\u6df1\u5165\u7814\u7a76\u3002AbTAC \u5229\u7528\u53cc\u7279\u5f02\u6027\u6297\u4f53\uff0c\u5176\u4e2d\u4e00\u53ea\u81c2\u9488\u5bf9 POI\uff0c\u53e6\u4e00\u53ea\u81c2\u9488\u5bf9 RNF43 E3 \u8fde\u63a5\u9176\u3002AbTACs \u53ef\u4ee5\u8bf1\u5bfc POIs \u5185\u5316\u548c\u968f\u540e\u7684\u6eb6\u9176\u4f53\u964d\u89e3\uff0c\u4f46\u786e\u5207\u7684\u964d\u89e3\u673a\u5236\u4ecd\u6709\u5f85\u8bc1\u5b9e\u3002<\/p>\n

3. PROTAC\u9776\u5411\u591a\u79cd\u86cb\u767d\u8d28\u7684\u5178\u578b\u5e94\u7528<\/p>\n

<\/h2>\n

\u7406\u8bba\u4e0a\uff0c\u5982\u679c\u6709\u5408\u9002\u7684\u5c0f\u5206\u5b50\u4e0e\u90a3\u4e9b POI \u7279\u5f02\u6027\u7ed3\u5408\uff0cPROTAC \u53ef\u4ee5\u964d\u89e3\u51e0\u4e4e\u6240\u6709\u7684\u7ec6\u80de\u5185\u86cb\u767d\u8d28\uff0c\u4f46\u5e76\u975e\u6240\u6709\u964d\u89e3\u5242\u90fd\u4f18\u4e8e\u5c0f\u5206\u5b50\u6291\u5236\u5242\u3002\u5728\u8fd9\u91cc\uff0c\u6211\u4eec\u603b\u7ed3\u4e86\u4e00\u4e9b\u5177\u6709\u660e\u663e\u6291\u5236\u6d3b\u6027\u7684\u5178\u578bPROTAC\u5206\u5b50\uff0c\u5176\u4e2d\u4e00\u4e9b\u5df2\u7ecf\u8fdb\u5165\u4e34\u5e8a\u8bd5\u9a8c\u9636\u6bb5\u3002<\/p>\n

3.1 \u7528\u4e8e\u9776\u5411\u86cb\u767d\u6fc0\u9176\u7684 PROTAC<\/h3>\n

\u4eba\u7c7b\u57fa\u56e0\u7ec4\u7f16\u7801\u8d85\u8fc7 500 \u79cd\u86cb\u767d\u6fc0\u9176\uff0c\u4f7f\u5176\u6210\u4e3a\u6700\u5927\u7684\u86cb\u767d\u8d28\u5bb6\u65cf\u3002\u76ee\u524d\uff0c\u4f20\u7edf\u7684\u5c0f\u5206\u5b50\u6291\u5236\u5242\u662f\u86cb\u767d\u6fc0\u9176\u76f8\u5173\u75be\u75c5\u7684\u4e3b\u8981\u6cbb\u7597\u9009\u62e9\u3002\u5927\u591a\u6570\u6fc0\u9176\u6291\u5236\u5242\u96c6\u4e2d\u4e8e\u6291\u5236\u53d7\u4f53\u916a\u6c28\u9178\u6fc0\u9176\uff08RTK\uff09\u3002\u7136\u800c\uff0c\u8010\u836f\u6027\u7684\u51fa\u73b0\u635f\u5bb3\u4e86\u4e34\u5e8a\u83b7\u76ca\uff0c\u56e0\u6b64\u8feb\u5207\u9700\u8981\u5e94\u7528\u65b0\u7684\u6cbb\u7597\u7b56\u7565\u6765\u514b\u670d\u8fd9\u4e00\u6311\u6218\u3002<\/p>\n

2013\u5e74\uff0cCrews\u56e2\u961f\u62a5\u9053\u4e86\u6700\u65e9\u7684\u6fc0\u9176PROTAC\uff0c\u7528\u4e8e\u9776\u5411PI3K\uff0c\u963b\u65ad\u4eba\u8868\u76ae\u751f\u957f\u56e0\u5b50\u53d7\u4f533\uff08ErbB3\uff09\u2013PI3K-Akt\uff08\u86cb\u767d\u6fc0\u9176B\uff09\u4fe1\u53f7\u901a\u8def\u3002\u8be5 PROTAC \u7531\u4e24\u4e2a\u62db\u52df POI \u548c E3 \u8fde\u63a5\u9176\u7684\u5f02\u7279\u5f02\u6027\u80bd\u5e8f\u5217\u7ec4\u6210\u3002ErbB3 \u884d\u751f\u5e8f\u5217\uff0c\u78f7\u9178\u5316\u540e\u53ef\u4e0e PI3K \u7ed3\u5408\u3002\u53e6\u4e00\u4e2a\u6e90\u81eaHIF1\u03b1 \u7684\u5e8f\u5217\u53ef\u4ee5\u901a\u8fc7 VHL \u8fdb\u884c\u9274\u5b9a\u3002\u4e24\u4e2a\u90e8\u5206\u901a\u8fc7 PEG \u8fde\u63a5\u4f53\u7ed3\u5408\uff0c\u5e76\u63ba\u5165\u7ec6\u80de\u7a7f\u900f\u5e8f\u5217\u4ee5\u6539\u5584\u7ec6\u80de\u901a\u900f\u6027\u3002\u7136\u800c\uff0c\u7531\u4e8e\u6e17\u900f\u6027\u5dee\u548c\u8fde\u63a5\u4f53\u4e0d\u7a33\u5b9a\uff0c\u8be5 PROTAC \u4ec5\u663e\u793a\u51fa\u4e2d\u7b49\u6548\u529b\u3002<\/p>\n

FAK \u662f\u4e00\u79cd\u916a\u6c28\u9178\u6fc0\u9176\uff0c\u8c03\u8282\u80bf\u7624\u8fdb\u5c55\u7684\u8bb8\u591a\u65b9\u9762\uff08\u4f8b\u5982\u4fb5\u88ad\u3001\u8f6c\u79fb\u548c\u8840\u7ba1\u751f\u6210\uff09\u3002FAK \u6fc0\u9176\u6291\u5236\u5242 defactinib \u5728\u6cbb\u7597\u6076\u6027\u80f8\u819c\u95f4\u76ae\u7624\u5e72\u764c\u7684\u4e34\u5e8a\u8bd5\u9a8c\u4e2d\u56e0\u7f3a\u4e4f\u7597\u6548\u800c\u5931\u8d25\u3002FAK \u8fd8\u5177\u6709\u9664\u6fc0\u9176\u4ee5\u5916\u7684\u652f\u67b6\u4f5c\u7528\uff0c\u4f46\u6fc0\u9176\u6291\u5236\u5242\u4e0d\u80fd\u6291\u5236\u6fc0\u9176\u72ec\u7acb\u7684\u529f\u80fd\u3002\u56e0\u6b64\uff0c\u8bbe\u8ba1\u4e86PROTAC-3\uff08\u56fe 2f) \u53ef\u6709\u6548\u8bf1\u5bfc FAK \u964d\u89e3\uff0cIC 50\u4e3a 6.5 nM \u3002PROTAC-3\u662f\u4e00\u79cd\u7531defactinib\u548cVHL\u914d\u4f53\u7ec4\u6210\u7684\u53cc\u529f\u80fd\u5206\u5b50\u3002\u5b83\u901a\u8fc7\u6709\u6548\u8bf1\u5bfc\u964d\u89e3\uff0c\u6709\u6548\u6291\u5236 FAK \u6fc0\u9176\u4f9d\u8d56\u6027\u4fe1\u53f7\u4f20\u5bfc\u548c\u6fc0\u9176\u4f9d\u8d56\u6027\u4fe1\u53f7\u4f20\u5bfc\u3002<\/p>\n

\u5e03\u9c81\u987f\u916a\u6c28\u9178\u6fc0\u9176 (BTK) \u662f TEC \u5bb6\u65cf\u975e\u53d7\u4f53\u80de\u8d28\u916a\u6c28\u9178\u6fc0\u9176\u7684\u6210\u5458\uff0c\u4e5f\u662f B \u7ec6\u80de\u53d7\u4f53 (BCR) \u4fe1\u53f7\u901a\u8def\u7684\u5173\u952e\u8c03\u8282\u56e0\u5b50\uff0c\u5728 B \u7ec6\u80de\u7684\u751f\u547d\u6d3b\u52a8\u4e2d\u53d1\u6325\u7740\u5173\u952e\u4f5c\u7528\uff0c\u4f8b\u5982\u589e\u6b96\u3001\u5b58\u6d3b\u548c\u5206\u5316\u3002BTK\u5728B\u7ec6\u80de\u80bf\u7624\u4e2d\u5e7f\u6cdb\u8868\u8fbe\uff0c\u4e34\u5e8a\u5e72\u9884\u4e00\u822c\u901a\u8fc7\u6291\u5236BTK\u7684\u6fc0\u9176\u6d3b\u6027\u6765\u8fdb\u884c\u30022013\u5e74\uff0cFDA\u6279\u51c6\u4e86\u9996\u521b\u7684\u5171\u4ef7\u6291\u5236\u5242\u4f0a\u5e03\u66ff\u5c3c\u7528\u4e8e\u6cbb\u7597\u591a\u79cdB\u7ec6\u80de\u6076\u6027\u80bf\u7624\u3002Ibrutinib \u4e0e BTK \u7684\u534a\u80f1\u6c28\u9178 481 (C481) \u5171\u4ef7\u7ed3\u5408\uff0cIC 50\u4e3a 0.5 nM \u3002\u7136\u800c\uff0c\u5df2\u7ecf\u53d1\u73b0 BTK (C481S) 481 \u4f4d\u7684\u534a\u80f1\u6c28\u9178\u5230\u4e1d\u6c28\u9178\u7a81\u53d8\u662f\u5bfc\u81f4\u4f0a\u5e03\u66ff\u5c3c\u83b7\u5f97\u6027\u8010\u836f\u7684\u539f\u56e0\u3002\u56e0\u6b64\uff0c\u4f7f\u7528 PROTAC \u6280\u672f\u8bf1\u5bfc BTK \u86cb\u767d\u964d\u89e3\u5df2\u6210\u4e3a\u4e00\u79cd\u6709\u524d\u9014\u7684\u66ff\u4ee3\u65b9\u6cd5\u3002\u8fc4\u4eca\u4e3a\u6b62\uff0c\u56db\u79cd BTK \u964d\u89e3\u5242\u5df2\u8fdb\u5165\u4e34\u5e8a\u8bd5\u9a8c\u3002\u5b83\u4eec\u5206\u522b\u662f\u6765\u81eaNurix Therapeutics\u7684NX-2127\uff08NCT04830137\uff09\u548cNX-5948\uff08NCT05131022 \uff09\uff0c\u6765\u81ea\u6d77\u601d\u79d1\u548c\u767e\u6d4e\u795e\u5dde\u7684HSK-29116\uff08 NCT04861779\uff09\u548cBGB-16673\uff08NCT05006716\uff09\u3002NX-2127\u5177\u6709BTK\u964d\u89e3\u5242\u548cIMiD\u65b0\u5e95\u7269\u964d\u89e3\u5242\u6d3b\u6027\u3002\u76ee\u524d\u6b63\u5728\u8fdb\u884c NX-2127 \u6cbb\u7597\u590d\u53d1\u6216\u96be\u6cbb\u6027 B \u7ec6\u80de\u6076\u6027\u80bf\u7624\u7684\u4e34\u5e8a\u8bd5\u9a8c\u3002\u4e34\u5e8a\u524d\u6570\u636e\u8868\u660e\uff0cNX-2127 \u53ef\u6709\u6548\u8bf1\u5bfc\u591a\u79cd\u764c\u7ec6\u80de\u7cfb\u548c\u4eba\u5916\u5468\u8840\u5355\u6838\u7ec6\u80de (PBMC) \u4e2dibrutinib\u654f\u611f\u7684 BTK WT\uff08\u91ce\u751f\u578b\uff09\u548cibrutinib\u8010\u836f\u7684 BTK C481S\u964d\u89e3\uff0cDC 50 \u2009< 5nM\u3002\u6b64\u5916\uff0cNX-2127\u6bd4ibrutinib\u66f4\u6709\u6548\u5730\u6291\u5236 TMD8 \u7ec6\u80de\u4e2dBTK C481S\u7684\u7ec6\u80de\u589e\u6b96\u3002NX-2127 \u7531\u6c99\u5229\u5ea6\u80fa IMiD \u7ec4\u6210\uff0c\u5177\u6709\u514d\u75ab\u8c03\u8282\u6d3b\u6027\u3002\u63ed\u793a\u6765\u90a3\u5ea6\u80fa\u5bfc\u81f4 CRBN \u65b0\u5e95\u7269 Aiolos (IKZF3) \u548c Ikaros (IKZF1) \u9009\u62e9\u6027\u6cdb\u7d20\u5316\u548c\u964d\u89e3\u3002\u5df2\u8868\u660e IKZF3 \u7684\u8fc7\u5ea6\u8868\u8fbe\u662f\u6162\u6027\u6dcb\u5df4\u7ec6\u80de\u767d\u8840\u75c5 (CLL) \u4e2d BTK \u6291\u5236\u5242\u8010\u836f\u6027\u7684\u9a71\u52a8\u56e0\u7d20\u3002\u56e0\u6b64\uff0cNX-2127\u5c06BTK\u964d\u89e3\u4e0eIKZF\u964d\u89e3\u76f8\u7ed3\u5408\u6709\u671b\u589e\u5f3a\u5176\u6297\u80bf\u7624\u6d3b\u6027\u3002NX-5948 \u662f Nurix Therapeutics \u8bbe\u8ba1\u7684\u53e6\u4e00\u79cd BTK \u964d\u89e3\u5242\u3002\u4e0e NX-2127 \u4e0d\u540c\uff0cNX-5948 \u7f3a\u4e4f\u514d\u75ab\u8c03\u8282\u6d3b\u6027\uff0c\u5e76\u4e14\u5728\u52a8\u7269\u6a21\u578b\u4e2d\u5177\u6709\u7a7f\u8fc7\u8840\u8111\u5c4f\u969c (BBB) \u7684\u80fd\u529b\u3002NX-5948 \u663e\u793a\u51fa\u4e0e\u4e34\u5e8a\u524d\u6570\u636e\u76f8\u4f3c\u7684\u6027\u80fd\uff0c\u4e34\u5e8a\u524d\u6570\u636e\u8868\u660e NX-5948 \u5728\u6dcb\u5df4\u7624\u7ec6\u80de\u7cfb\u548c PBMC \u4e2d\u8bf1\u5bfc BTK \u964d\u89e3\uff08< 1 nM \u65f6\u964d\u89e3\u6548\u7387\u4e3a 50%\uff09\u3002<\/p>\n

3.2 \u7528\u4e8e\u9776\u5411\u6838\u53d7\u4f53\u7684 PROTAC<\/h3>\n

\u6838\u53d7\u4f53\uff08NR\uff09\u5c5e\u4e8e\u8f6c\u5f55\u56e0\u5b50\u5bb6\u65cf\u3002\u4e0e\u5176\u4ed6\u4f20\u7edf\u8f6c\u5f55\u56e0\u5b50\u4e0d\u540c\uff0c\u5176\u4e3b\u8981\u529f\u80fd\u662f\u5c06\u5916\u90e8\u4fe1\u53f7\u8f6c\u6362\u4e3a\u8f6c\u5f55\u8f93\u51fa\u3002\u5178\u578b\u7684 NR \u5305\u62ec\u4e09\u4e2a\u7ed3\u6784\u57df\uff1a\u4e24\u4e2a\u5206\u522b\u7ed3\u5408 DNA \u548c\u914d\u4f53\u7684\u7ed3\u6784\u57df\uff0c\u4ee5\u53ca\u4e00\u4e2a\u5728\u5e8f\u5217\u548c\u5927\u5c0f\u65b9\u9762\u9ad8\u5ea6\u53ef\u53d8\u7684\u975e\u7ed3\u6784\u5316 N \u672b\u7aef\u8c03\u8282\u7ed3\u6784\u57df\u3002\u914d\u4f53\u6fc0\u52a8\u5242\u7ed3\u5408\u4f1a\u4ea7\u751f\u6784\u8c61\u53d8\u5316\uff0c\u5bfc\u81f4\u6838\u5b9a\u4f4d\u4fe1\u53f7 (NLS) \u66b4\u9732\uff0c\u4ece\u800c\u4f7f NR \u6613\u4f4d\u81f3\u7ec6\u80de\u6838\u5e76\u7ed3\u5408\u54cd\u5e94\u5143\u4ef6\u3002\u4e0e\u914d\u4f53\u7ed3\u5408\u57df\u7ed3\u5408\u7684\u5c0f\u5206\u5b50\u6291\u5236\u5242\u88ab\u8bbe\u8ba1\u7528\u6765\u6fc0\u6d3b\u6216\u963b\u65ad\u6838\u53d7\u4f53\u7684\u4fe1\u53f7\u8f6c\u5bfc\u529f\u80fd\u3002\u7136\u800c\uff0c\u5c0f\u5206\u5b50\u6291\u5236\u5242\u6709\u51e0\u4e2a\u7f3a\u70b9\u3002\u4f8b\u5982\uff0c\u76ee\u524d\u5bf9\u6291\u5236\u5242\u6982\u5ff5\u7684\u7406\u89e3\u5c1a\u4e0d\u6e05\u695a\uff0c\u56e0\u4e3a\u5f53 AR \u57fa\u56e0\u8fc7\u5ea6\u8868\u8fbe\u6216\u7a81\u53d8\u65f6\uff0c\u6301\u7eed\u7684 AR \u62ee\u6297\u5242\u88ab\u8bc1\u660e\u662f\u6fc0\u52a8\u5242\u3002\u6b64\u5916\uff0c\u5b64\u513fNRs\u7684\u4e00\u4e9b\u914d\u4f53\u5c1a\u672a\u786e\u5b9a\uff0c\u4ece\u800c\u4f7f\u5f97\u9776\u5411NRs\u6cbb\u7597\u75be\u75c5\u53d8\u5f97\u66f4\u52a0\u590d\u6742\u3002PROTAC \u6280\u672f\u7684\u51fa\u73b0\u4f7f\u5f97\u9488\u5bf9\u66f4\u5e7f\u6cdb\u7684 NR \u6210\u4e3a\u53ef\u80fd\u3002AR\u3001ER\u7b49NRs\u53c2\u4e0e\u4f53\u5185\u5404\u79cd\u91cd\u8981\u7684\u751f\u7406\u8fdb\u7a0b\uff0c\u4e0e\u524d\u5217\u817a\u764c\u3001\u4e73\u817a\u764c\u5bc6\u5207\u76f8\u5173\u3002\u56e0\u6b64\uff0c\u4e00\u7cfb\u5217\u9488\u5bf9ER\u6216AR\u7684PROTAC\u88ab\u5f00\u53d1\u51fa\u6765\u3002<\/p>\n

AR\u4fe1\u53f7\u4f20\u5bfc\u5bf9\u4e8e\u524d\u5217\u817a\u6b63\u5e38\u529f\u80fd\u7684\u53d1\u80b2\u548c\u7ef4\u6301\u81f3\u5173\u91cd\u8981\u3002AR\u4e0d\u4ec5\u5728\u7ef4\u6301\u808c\u8089\u9aa8\u9abc\u548c\u7537\u6027\u6027\u76f8\u5173\u529f\u80fd\u4e2d\u53d1\u6325\u7740\u5173\u952e\u4f5c\u7528\uff0c\u800c\u4e14\u5728\u524d\u5217\u817a\u764c\u7684\u8fdb\u5c55\u4e2d\u4e5f\u53d1\u6325\u7740\u5173\u952e\u4f5c\u7528\u3002\u4f7f\u7528\u6069\u6742\u9c81\u80fa\u548c\u963f\u5e15\u9c81\u80fa\u7b49 AR \u62ee\u6297\u5242\u6291\u5236 AR \u529f\u80fd\u662f\u6cbb\u7597\u524d\u5217\u817a\u764c\u7684\u5e38\u89c1\u7b56\u7565\u3002\u4e0d\u5e78\u7684\u662f\uff0c\u63a5\u53d7\u6297\u96c4\u6fc0\u7d20\u6cbb\u7597\u7684\u60a3\u8005\u6700\u7ec8\u4f1a\u51fa\u73b0\u53bb\u52bf\u62b5\u6297\u3002PROTACs \u4f5c\u4e3a\u4e00\u79cd\u66ff\u4ee3\u7684\u6f5c\u5728\u6cbb\u7597\u65b9\u6cd5\u51fa\u73b0\uff0c\u4ee5\u5f25\u8865 AR \u6291\u5236\u5242\u7684\u7f3a\u70b9\u3002\u7531\u6b64\uff0c\u5408\u6210\u4e86\u4e00\u79cd\u6709\u6548\u7684 AR PROTAC ARCC-4\uff08\u56fe 2g)\uff0c\u5176\u7531\u6069\u6742\u9c81\u80fa\u884d\u751f\u7269\u548c\u62db\u52dfVHL\u7684E3\u914d\u4f53\u7ec4\u6210\u3002\u4e0e\u5176\u6bcd\u4f53\u6291\u5236\u5242\u6069\u6742\u9c81\u80fa\u76f8\u6bd4\uff0cARCC-4\u53ef\u4ee5\u6709\u6548\u964d\u89e3AR\u548c\u957f\u671f\u4f7f\u7528\u4e34\u5e8a\u6291\u5236\u5242\u5f15\u8d77\u7684AR\u7a81\u53d8\u4f53\uff0c\u4e14\u4e0d\u4f1a\u5bfc\u81f4\u8010\u836f\u6027\u7684\u5b58\u5728\u3002\u4f17\u6240\u5468\u77e5\uff0cARV-110\uff08\u56fe 2g)\u662f\u7b2c\u4e00\u4e2a\u5904\u4e8e\u4e34\u5e8a\u8bd5\u9a8c\u4e2d\u7684AR\u9776\u5411PROTAC\u3002\u6700\u65b0\u7684\u4e34\u5e8a\u8bd5\u9a8c\u6570\u636e\u8868\u660eARV-110\u5177\u6709\u53ef\u63a5\u53d7\u7684\u5b89\u5168\u6027\u3002\u6700\u5927\u8010\u53d7\u5242\u91cf (MTD) \u5c1a\u672a\u786e\u5b9a\uff0c\u63a8\u8350\u7684 2 \u671f\u5242\u91cf (RP2D) \u7684\u786e\u5b9a\u4ecd\u5728\u7ee7\u7eed\u3002\u6b64\u5916\uff0cARV-110 \u5df2\u5728\u8f6c\u79fb\u6027\u53bb\u52bf\u62b5\u6297\u6027\u524d\u5217\u817a\u764c (mCRPC) \u60a3\u8005\u670d\u7528\u6069\u6742\u9c81\u80fa\u548c\/\u6216\u963f\u6bd4\u7279\u9f99\u540e\u8868\u73b0\u51fa\u6297\u80bf\u7624\u6d3b\u6027 \u3002\u6700\u8fd1\uff0c\u738b\u7684\u56e2\u961f\u62a5\u9053\u4e86\u4e24\u79cd\u9ad8\u6548\u4e14\u53ef\u53e3\u670d\u751f\u7269\u5229\u7528\u7684 AR PROTAC\uff0cARD-2128 \u548c ARD-2585\uff08\u56fe 2g\uff09\u3002ARD-2128 \u662f\u4e00\u79cd\u4f18\u5316\u7684 AR \u62ee\u6297\u5242\uff0c\u901a\u8fc7\u521a\u6027\u63a5\u5934\u4e0e\u6c99\u5229\u5ea6\u80fa\u8fde\u63a5\uff0c\u5728\u5c0f\u9f20\u4e2d\u5b9e\u73b0\u4e86 67% \u7684\u53e3\u670d\u751f\u7269\u5229\u7528\u5ea6\u548c\u6bd4\u6069\u6742\u9c81\u80fa\u66f4\u597d\u7684\u6297\u80bf\u7624\u6d3b\u6027\u3002ARD-2585 \u5305\u542b\u4e0e ARD-2128 \u76f8\u540c\u7684 CRBN \u914d\u4f53\uff0c\u5728 VCaP \u7ec6\u80de\u7cfb\u4e2d\u8fbe\u5230 \u2264 0.1 nM \u7684 DC50\u503c\uff0c\u5728\u5c0f\u9f20\u4e2d\u8fbe\u5230 51% \u7684\u53e3\u670d\u751f\u7269\u5229\u7528\u5ea6\u3002<\/p>\n

\u4e73\u817a\u764c\u662f\u4e00\u79cd\u4e73\u817a\u7ec4\u7ec7\u53d1\u751f\u764c\u53d8\u7684\u6076\u6027\u80bf\u7624\uff0c\u60a3\u8005\u901a\u5e38\u662f\u5973\u6027\u7fa4\u4f53\u3002\u6839\u636e\u80bf\u7624\u53d7\u4f53\u7684\u72b6\u6001\uff0c\u4e73\u817a\u764c\u53ef\u5206\u4e3a\u4e09\u79cd\u7c7b\u578b\uff1a\u96cc\u6fc0\u7d20\u53d7\u4f53\u9633\u6027\uff08ER+\uff09\u3001\u4eba\u8868\u76ae\u751f\u957f\u56e0\u5b50\u53d7\u4f532\u9633\u6027\uff08HER2+\uff09\u548c\u4e09\u9634\u6027\u4e9a\u578b\uff08ER-\u3001PR-\u3001HER2\uff09 -\uff09\u3002\u5176\u4e2d\uff0cER+\u4e73\u817a\u764c\u6700\u5e38\u88ab\u8bca\u65ad\u51fa\u3002ER\u662f\u6838\u53d7\u4f53\u5bb6\u65cf\u7684\u6210\u5458\uff0cER\u03b1\u548cER\u03b2\u8c03\u8282\u96cc\u6fc0\u7d20\u7684\u57fa\u56e0\u8868\u8fbe\u3002\u7136\u800c\uff0cER\u03b1 \u5df2\u88ab\u8bc1\u5b9e\u4e3b\u8981\u8d1f\u8d23\u5973\u6027\u751f\u6b96\u7cfb\u7edf\u548c\u4e73\u817a\u7ec4\u7ec7\u4e2d\u96cc\u6fc0\u7d20\u4fe1\u53f7\u7684\u8f6c\u6362\u3002\u5927\u591a\u6570\u9009\u62e9\u6027\u96cc\u6fc0\u7d20\u53d7\u4f53\u964d\u89e3\u5242\uff08SERD\uff09\u65e8\u5728\u9776\u5411 ER\u03b1 \u6765\u6cbb\u7597 ER + \u4e73\u817a\u764c\u3002SERD \u662f\u4e00\u7c7b\u4e0e ER\u03b1 \u7ed3\u5408\u5e76\u968f\u540e\u88ab\u86cb\u767d\u9176\u4f53\u964d\u89e3\u7684\u5c0f\u5206\u5b50\u3002\u6c1f\u7ef4\u53f8\u7fa4(Fulvestrant)\u662f\u552f\u4e00\u88ab\u6279\u51c6\u5e76\u901a\u8fc7\u6bcf\u6708\u808c\u8089\u6ce8\u5c04\u7528\u4e8e\u6cbb\u7597\u7edd\u7ecf\u540e\u5973\u6027\u4e73\u817a\u764c\u7684 SERD\u3002\u9488\u5bf9\u6c1f\u7ef4\u53f8\u7fa4\u53e3\u670d\u751f\u7269\u5229\u7528\u5ea6\u5dee\u7684\u7f3a\u70b9\uff0c\u4e00\u7cfb\u5217SERD\u5206\u5b50\u88ab\u5f00\u53d1\u51fa\u6765\u3002\u4f46SERD\u5206\u5b50\u4e0d\u80fd\u5b8c\u5168\u964d\u89e3ER\uff0c\u957f\u671f\u4f7f\u7528\u4f1a\u5bfc\u81f4\u8010\u836f\u6027\u3002PROTAC\u6280\u672f\u63d0\u4f9b\u4e86\u53e6\u4e00\u79cd\u6cbb\u7597\u9009\u62e9\u3002Arvinas \u5f00\u53d1\u4e86\u4e00\u79cd\u9488\u5bf9 ER \u7684 PROTAC\uff0cARV-471\uff08\u56fe 2h)\uff0c\u7ecfFDA\u6279\u51c6\u8fdb\u5165\u4e34\u5e8a\u8bd5\u9a8c\uff0c\u7528\u4e8e\u6cbb\u7597\u5c40\u90e8\u665a\u671f\u6216\u8f6c\u79fb\u6027ER\u9633\u6027\/HER2\u9634\u6027\u4e73\u817a\u764c\u60a3\u8005\u3002\u4e2d\u671f\u8bd5\u9a8c\u7ed3\u679c\u663e\u793a\uff0cARV-471\u53ef\u663e\u7740\u964d\u4f4e\u80bf\u7624\u7ec4\u7ec7\u4e2dER\u7684\u8868\u8fbe\u6c34\u5e73\uff0c\u5e73\u5747\u964d\u4f4e62%\uff0c\u6700\u9ad8\u53ef\u8fbe90%\u3002\u6b64\u5916\uff0cARV-471 \u53ef\u4ee5\u5728\u591a\u79cd ER \u9633\u6027\u4e73\u817a\u764c\u7ec6\u80de\u7cfb\u4e2d\u964d\u89e3\u91ce\u751f\u578b\u548c\u4e34\u5e8a\u76f8\u5173\u7684 ER\u03b1 \u7a81\u53d8\u4f53\uff08Y537S \u548c D538G\uff09\uff0c\u5176DC 50\u503c\u7ea6\u4e3a 2 nM\u3002<\/p>\n

3.3 \u7528\u4e8e\u9776\u5411\u8f6c\u5f55\u56e0\u5b50\u7684 PROTAC<\/h3>\n

\u8f6c\u5f55\u56e0\u5b50\uff08TF\uff09\u662f\u4e00\u7c7b\u4e0eDNA\u7279\u5b9a\u5e8f\u5217\u7ed3\u5408\u4ee5\u8c03\u8282\u57fa\u56e0\u8f6c\u5f55\u8fc7\u7a0b\u7684\u86cb\u767d\u8d28\u3002\u8f6c\u5f55\u56e0\u5b50\u5728\u589e\u6b96\u3001\u5206\u5316\u548c\u6b7b\u4ea1\u7b49\u591a\u79cd\u7ec6\u80de\u529f\u80fd\u4e2d\u53d1\u6325\u7740\u5173\u952e\u4f5c\u7528\u3002\u9664\u6838\u53d7\u4f53\u5916\uff0c\u76f4\u63a5\u9776\u5411\u8f6c\u5f55\u56e0\u5b50\u5bf9\u4e8e\u5c0f\u5206\u5b50\u6291\u5236\u5242\u6765\u8bf4\u5c24\u5176\u5177\u6709\u6311\u6218\u6027\uff0c\u56e0\u6b64\u51e0\u5341\u5e74\u6765\u5b83\u4eec\u4e00\u76f4\u88ab\u8ba4\u4e3a\u662f\u201c\u4e0d\u53ef\u6210\u836f\u7684\u86cb\u767d\u8d28\u201d \u3002\u56e0\u6b64\uff0c\u8bf1\u5bfc\u86cb\u767d\u8d28\u964d\u89e3\u6210\u4e3a\u8f6c\u5f55\u56e0\u5b50\u7684\u4e00\u79cd\u6f5c\u5728\u65b9\u5f0f\u3002\u6839\u636eDNA\u7ed3\u5408\u57df\u7684\u5177\u4f53\u7ed3\u6784\uff0c\u8f6c\u5f55\u56e0\u5b50\u53ef\u5206\u4e3a\u6570\u5341\u4e2a\u5bb6\u65cf\u3002\u503c\u5f97\u6ce8\u610f\u7684\u662f\uff0cC2H2\u950c\u6307\u3001\u540c\u6e90\u57df\u548c\u87ba\u65cb-\u73af-\u87ba\u65cb\u5bb6\u65cf\u5360\u8f6c\u5f55\u56e0\u5b50\u603b\u6570\u768480%\u4ee5\u4e0a\u3002<\/p>\n

\u4fe1\u53f7\u8f6c\u5bfc\u548c\u8f6c\u5f55\u6fc0\u6d3b\u56e0\u5b50 3 (STAT3) \u662f\u4e00\u79cd\u5173\u952e\u7684\u6838\u8f6c\u5f55\u56e0\u5b50\uff0c\u5728\u916a\u6c28\u9178 705 \u4e0a\u88ab\u78f7\u9178\u5316\uff0c\u5e76\u6574\u5408\u7ec6\u80de\u56e0\u5b50\u548c\u751f\u957f\u56e0\u5b50\u4fe1\u53f7\u4f20\u5bfc\u4ee5\u8c03\u8282\u4e00\u7cfb\u5217\u7ec6\u80de\u8fc7\u7a0b\u3002STAT\u5bb6\u65cf\u75317\u79cd\u86cb\u767d\u7ec4\u6210\uff0c\u5176\u4e2dSTAT3\u5df2\u88ab\u8bc1\u660e\u5728\u591a\u79cd\u764c\u75c7\u4e2d\u8fc7\u5ea6\u8868\u8fbe\uff0c\u5c24\u5176\u662f\u4e73\u817a\u764c\u3002\u9776\u5411 STAT3 \u662f\u6cbb\u7597\u5404\u79cd\u764c\u75c7\u3001\u708e\u75c7\u548c\u81ea\u8eab\u514d\u75ab\u6027\u75be\u75c5\u7684\u666e\u904d\u7b56\u7565\u3002STAT3\u5728Tyr705\u4f4d\u70b9\u7684\u78f7\u9178\u5316\u53ef\u4ee5\u89e6\u53d1\u5176\u4e8c\u805a\u5316\uff0c\u5e76\u4e14\u4e0e\u9776\u57fa\u56e0\u7684\u8f6c\u5f55\u8c03\u63a7\u5bc6\u5207\u76f8\u5173\u3002STAT3\u4e8c\u805a\u5316\u4f9d\u8d56\u4e8e\u4e24\u4e2a\u5355\u4f53\u7684Src\u540c\u6e902(SH2)\u7ed3\u6784\u57df\u4e4b\u95f4\u7684\u76f8\u4e92\u4f5c\u7528\u3002\u57fa\u4e8e\u8fd9\u4e00\u673a\u5236\uff0c\u7814\u7a76\u4eba\u5458\u70ed\u8877\u4e8e\u5bfb\u627e\u4f5c\u7528\u4e8eSH2\u7ed3\u6784\u57df\u7684\u5c0f\u5206\u5b50\u6291\u5236\u5242\uff0c\u4ee5\u963b\u65adSTAT3\u4e8c\u805a\u5316\u548c\u8f6c\u5f55\u6d3b\u6027\u3002\u7136\u800c\uff0c\u7531\u4e8eSTAT\u5bb6\u65cf\u6210\u5458\u4e4b\u95f4\u5b58\u5728\u7ed3\u6784\u540c\u6e90\u6027\uff0c\u4e00\u4e9b\u4f5c\u7528\u4e8eSTAT3 SH2\u7ed3\u6784\u57df\u7684\u6291\u5236\u5242\u5df2\u8868\u73b0\u51fa\u6709\u9650\u7684\u4e34\u5e8a\u4ef7\u503c\uff0c\u8fd9\u4e3a\u7279\u5b9aSTAT3\u6291\u5236\u5242\u7684\u5f00\u53d1\u5e26\u6765\u4e86\u969c\u788d\u3002\u53e6\u4e00\u4e2a\u7a81\u51fa\u7684\u95ee\u9898\u662f\uff0c\u5355\u4e2a STAT3 \u86cb\u767d\u4ecd\u7136\u5177\u6709\u8f6c\u5f55\u6d3b\u6027\uff0c\u56e0\u6b64\u5f00\u53d1 STAT3 SH2 \u7ed3\u6784\u57df\u7684\u6291\u5236\u5242\u5e76\u4e0d\u662f\u5b8c\u5168\u6291\u5236 STAT3 \u6d3b\u6027\u7684\u53ef\u884c\u65b9\u6cd5\u3002PROTAC \u4f5c\u4e3a\u9776\u5411\u86cb\u767d\u964d\u89e3\u7684\u65b0\u578b\u7597\u6cd5\u5177\u6709\u5e7f\u9614\u7684\u524d\u666f\u3002\u5728\u8fd9\u91cc\uff0c\u6211\u4eec\u4ecb\u7ecd\u4e86\u4e00\u79cd\u7279\u5b9a\u4e14\u6709\u6548\u7684 STAT3 PROTAC\u3002\u767d\u7b49\u4eba\u3002\u62a5\u9053\u4e86\u7b2c\u4e00\u4e2aSTAT3 PROTAC SD-36\uff08\u56fe 2i)\u4e0d\u4ec5\u80fd\u6709\u6548\u3001\u7279\u5f02\u6027\u5730\u964d\u89e3STAT3\uff0c\u800c\u4e14\u5177\u6709\u6297\u767d\u8840\u75c5\u548c\u6dcb\u5df4\u7624\u7ec6\u80de\u7cfb\u589e\u6b96\u6d3b\u6027\u3002SD-36 \u7531\u9009\u62e9\u6027 STAT3 \u6291\u5236\u5242 SI-109 \u548c\u6765\u90a3\u5ea6\u80fa\u7ec4\u6210\uff0c\u662f PROTAC \u5982\u4f55\u5e94\u7528\u4e8e\u9776\u5411\u8f6c\u5f55\u56e0\u5b50\u7b49\u6311\u6218\u6027\u86cb\u767d\u8d28\u7684\u5178\u578b\u6210\u529f\u8303\u4f8b\u3002<\/p>\n

4. PROTAC\u7684\u8bbe\u8ba1\u548c\u5f00\u53d1<\/p>\n

<\/h2>\n

PROTACs\u7684\u964d\u89e3\u6d3b\u6027\u4e0d\u4ec5\u53d6\u51b3\u4e8e\u4e24\u7aef\u4e0e\u5176\u5404\u81ea\u9776\u6807\u7684\u4eb2\u548c\u529b\uff0c\u8fd8\u4f9d\u8d56\u4e8e\u80fd\u591f\u5f62\u6210\u7a33\u5b9aPPI\u7684\u4e09\u5143\u590d\u5408\u7269\u7684\u5f62\u6210\u3002\u76ee\u524d\uff0cPROTAC\u7684\u6784\u5efa\u5f88\u5927\u7a0b\u5ea6\u4e0a\u4f9d\u8d56\u4e8e\u7ecf\u9a8c\u5206\u6790(empirical analyses)\u548c\u6784\u6548\u5173\u7cfb\uff08SAR\uff09\u7814\u7a76\u3002\u7136\u800c\uff0c\u5408\u6210\u96be\u5ea6\u5bf9\u5feb\u901f\u5408\u6210\u5927\u91cf PROTAC \u5316\u5408\u7269\u5e93\u63d0\u51fa\u4e86\u91cd\u5927\u9650\u5236\u3002\u901a\u8fc7\u5206\u6790\u548c\u603b\u7ed3\u5df2\u53d1\u8868\u7684PROTAC\u7ed3\u6784\uff0c\u6211\u4eec\u5c06\u63d0\u4f9bPROTAC\u8bbe\u8ba1\u7684\u5e38\u89c4\u7b56\u7565\uff0c\u4ee5\u52a0\u901fPROTAC\u7684\u53d1\u73b0\u3002\u6b64\u5916\uff0c\u8fd8\u5217\u51fa\u4e86\u4e00\u4e9b\u6700\u8fd1\u62a5\u9053\u7684 PROTAC\uff0c\u5b83\u4eec\u62db\u52df\u5177\u6709\u76f8\u5e94\u964d\u89e3\u6d3b\u6027\u7684\u4f20\u7edf E3 \u8fde\u63a5\u9176\uff08\u8868 4\uff09\u3002<\/p>\n

\u8868 4. 2019\u5e74\u4ee5\u6765\u62a5\u9053\u7684PROTAC\u4ee3\u8868\u6027\u5316\u5408\u7269<\/h3>\n<\/p>\n

4.1 E3\u8fde\u63a5\u9176\u53ca\u5176\u914d\u4f53<\/h3>\n

\u5728\u5df2\u9274\u5b9a\u7684 600 \u591a\u79cd\u8fde\u63a5\u9176\u4e2d\uff0c\u53ea\u6709\u5c11\u6570\u5177\u6709\u5c0f\u5206\u5b50\u914d\u4f53\u7684\u8fde\u63a5\u9176\u5df2\u7528\u4e8e PROTAC \u9776\u5411\u3002\u6211\u4eec\u5217\u51fa\u4e86\u5e38\u7528\u7684 E3 \u8fde\u63a5\u9176\u53ca\u5176\u914d\u4f53\uff08\u56fe 3\uff09\u3002\u603b\u7ed3\u5206\u6790\u4e86\u8fd1 20 \u5e74\u6765\u53d1\u8868\u7684\u9ad8\u6d3b\u6027 PROTAC \u7684\u7ed3\u6784\uff0c\u53d1\u73b0\u6700\u5e38\u7528\u7684\u662f CRBN\u3001VHL \u548c cIAP \u914d\u4f53\uff0c\u5176\u4e2d CRBN \u5360 60.1%\uff0cVHL \u5360 30.1%\uff0ccIAP \u5360 5.5%\u3002\u4e3b\u8981\u539f\u56e0\u662fCRBN\u5728\u9ad8\u4e30\u5ea6\u7684\u7ec4\u7ec7\u4e2d\u5e7f\u6cdb\u8868\u8fbe\uff0c\u5e76\u4e14\u57fa\u4e8eCRBN\u7684PROTAC\u5177\u6709\u66f4\u597d\u7684\u964d\u89e3\u6548\u7387\u3002\u6b64\u5916\uff0c\u4e0eVHL\u914d\u4f53\u76f8\u6bd4\uff0cCRBN\u914d\u4f53\u5177\u6709\u66f4\u597d\u7684\u7c7b\u836f\u7279\u6027\u3002\u62db\u52df MDM2 \u548c cIAP \u7684 PROTAC \u901a\u5e38\u5177\u6709\u8f83\u9ad8\u7684\u5206\u5b50\u91cf\u548c\u8f83\u5dee\u7684\u7ec4\u7ec7\u6e17\u900f\u6027\uff0c\u8868\u660e\u53e3\u670d\u751f\u7269\u5229\u7528\u5ea6\u53ef\u80fd\u662f\u4e00\u4e2a\u6f5c\u5728\u7684\u95ee\u9898\u3002\u5176\u4ed6\u4e00\u4e9bE3\u8fde\u63a5\u9176\u5982DCAF11\u3001DCAF15\u3001DCAF16\u3001KEAP1\u548cRNF114\u7b49\u8f83\u5c11\u4f7f\u7528\uff0c\u539f\u56e0\u5982\u4e0b\uff1a\u5b83\u4eec\u7684\u914d\u4f53\u6765\u6e90\u4e8e\u5929\u7136\u4ea7\u7269\uff0c E3\u8fde\u63a5\u9176\u4eb2\u548c\u529b\u5dee\uff0c\u5408\u6210\u56f0\u96be\uff0c\u4e14\u5927\u591a\u6570E3\u8fde\u63a5\u9176\u662f\u7531\u4e0d\u53ef\u9006\u7684PROTACs\u62db\u52df\u7684\uff0c\u5176\u964d\u89e3\u6d3b\u6027\u8f83\u5dee\uff0c\u5e76\u5177\u6709\u4e00\u5b9a\u7684\u6f5c\u5728\u6bd2\u6027\u3002\u503c\u5f97\u6ce8\u610f\u7684\u662f\uff0c\u4e0d\u540c\u7684\u62db\u52df E3 \u8fde\u63a5\u9176\u5df2\u88ab\u8bc1\u660e\u53ef\u8bf1\u5bfc\u4e0d\u540c\u7a0b\u5ea6\u7684\u86cb\u767d\u8d28\u964d\u89e3\u3002\u4e3b\u8981\u539f\u56e0\u662f\uff1a\u4e0d\u540c\u7ec6\u80de\u4e2dE3\u8fde\u63a5\u9176\u7684\u8868\u8fbe\u6c34\u5e73\u4e0d\u540c\uff0c\u53ef\u80fd\u5bfc\u81f4\u964d\u89e3\u6548\u7387\u4e0d\u540c\u3002\u5e76\u4e14\u6709\u4e9b\u86cb\u767d\u8d28\u5bf9\u4e8e\u4e0d\u540c\u7684E3\u8fde\u63a5\u9176\u5177\u6709\u4e0d\u540c\u7a0b\u5ea6\u7684\u9009\u62e9\u6027\u3002\u56e0\u6b64\uff0c\u5728\u8bbe\u8ba1PROTAC\u7684\u8fc7\u7a0b\u4e2d\uff0c\u5e94\u4f18\u5148\u9009\u62e9\u9488\u5bf9CRBN\u6216VHL\u7684\u914d\u4f53\uff0c\u56e0\u4e3a\u8fd9\u4e24\u79cdE3\u8fde\u63a5\u9176\u7684\u5e94\u7528\u8303\u56f4\u6700\u5e7f\u3002\u4f5c\u4e3a\u8bf4\u660e\u6027\u5b9e\u4f8b\uff0cARV-110\u548cARV-471\u90fd\u9009\u62e9CRBN\u8fde\u63a5\u9176\u4f5c\u4e3aE3\u914d\u4f53\u3002\u5728\u8fd9\u91cc\uff0c\u6211\u4eec\u56de\u987e\u4e86 PROTAC \u8bbe\u8ba1\u4e2d\u4f7f\u7528\u7684\u4f20\u7edf E3 \u8fde\u63a5\u9176\u53ca\u5176\u914d\u4f53\u3002<\/p>\n<\/p>\n

\u56fe3 \u7528\u4e8e PROTAC \u7684 E3 \u8fde\u63a5\u9176\u7684\u4ee3\u8868\u6027\u5c0f\u5206\u5b50\u914d\u4f53\u3002\u84dd\u70b9\u8868\u793a\u9002\u5f53\u7684\u94fe\u63a5\u5b50\u7ed3\u5408\u4f4d\u70b9<\/p>\n

4.2 PROTAC\u7684\u94fe\u63a5\u5b50\u8bbe\u8ba1\u7b56\u7565<\/h3>\n

1. \u8fde\u63a5\u5b50\u7c7b\u578b<\/h4>\n

Maple \u7814\u7a76\u7ec4\u5efa\u7acb\u4e86\u4e00\u4e2a\u5305\u542b 400 \u591a\u4e2a\u5df2\u53d1\u8868\u7684 PROTAC \u7684\u6570\u636e\u5e93\uff0c\u4ee5\u627e\u5230\u5df2\u5e94\u7528\u4e8e PROTAC \u7684\u4e00\u822c\u539f\u7406\u3002\u6570\u636e\u5e93\u4e2d\u94fe\u63a5\u5b50\u7ed3\u6784\u7684\u6458\u8981\uff08\u8868 5\uff09\u63ed\u793a\u4e86\u8fc4\u4eca\u4e3a\u6b62 PROTAC \u8bbe\u8ba1\u4e2d\u5e38\u7528\u7684\u8fde\u63a5\u4f53\u662f PEG \u548c\u4e0d\u540c\u957f\u5ea6\u7684\uff08\u4e0d\uff09\u9971\u548c\u70f7\u70c3\u94fe\u3002\u7531\u4e8e\u5316\u5b66\u5408\u6210\u7b80\u4fbf\u7684\u7279\u70b9\uff0c\u70f7\u57fa\u63a5\u5934\u901a\u5e38\u7528\u4e8e\u5408\u6210 PROTAC \u5206\u5b50\uff0c\u4ee5\u786e\u5b9a\u6700\u4f73\u63a5\u5934\u957f\u5ea6\u3002\u7136\u800c\uff0c\u7531\u4e8e PROTAC \u7684\u9ad8\u758f\u6c34\u6027\uff0c\u70f7\u57fa\u8fde\u63a5\u5b50\u7684\u5f15\u5165\u53ef\u80fd\u4f1a\u964d\u4f4e PROTAC \u7684\u7ec6\u80de\u6e17\u900f\u6027\u3002\u542b\u6709\u6742\u539f\u5b50\uff08\u6c27\u539f\u5b50\u6216\u6c2e\u539f\u5b50\uff09\u7684\u70f7\u57fa\u94fe\u6bd4\u5355\u72ec\u7684\u70f7\u57fa\u94fe\u5177\u6709\u6539\u5584\u7684\u4eb2\u6c34\u6027\u3002\u6b64\u5916\uff0c\u63ba\u5165PEG\u94fe\u53ef\u4ee5\u589e\u5f3aPROTAC\u7684\u6eb6\u89e3\u5ea6\u548c\u7ec6\u80de\u5bf9PROTAC\u7684\u5438\u6536\u3002\u8d85\u8fc7\u4e00\u534a\u5df2\u53d1\u8868\u7684 PROTAC \u7ed3\u6784\u5305\u542b\u70f7\u57fa\u548c PEG \u57fa\u5e8f\u3002PROTAC \u4e2d\u52a0\u5165\u4e86\u70f7\u57fa\u3001PEG \u548c\u4e59\u4e8c\u9187\u94fe\u4ee5\u63d0\u9ad8\u7075\u6d3b\u6027\u3002\u7136\u800c\uff0c\u5b83\u4eec\u7684\u5f15\u5165\u4f1a\u5f71\u54cd PROTAC \u7684\u836f\u4ee3\u52a8\u529b\u5b66 (PK) \u7279\u6027\u3002\u8fd1\u5e74\u6765\uff0c\u7ebf\u6027\u8fde\u63a5\u57fa\u9010\u6e10\u88ab\u521a\u6027\u8fde\u63a5\u57fa\u53d6\u4ee3\uff0c\u4f8b\u5982\u7094\u70c3\u548c\u9971\u548c\u6742\u73af\uff08\u54cc\u55ea\u548c\u54cc\u5576\uff09\u3002\u82b3\u73af\u6216\u7094\u94fe\u7684\u5f15\u5165\u8d4b\u4e88\u4e86\u4e00\u5b9a\u7684\u521a\u6027\u5e76\u4fc3\u8fdb\u7a33\u5b9a\u7684\u4e09\u5143\u7edc\u5408\u7269\u7684\u5f62\u6210\u3002\u5b83\u8fd8\u4fc3\u8fdb PROTAC \u7684\u6eb6\u89e3\u5ea6\u548c\u7ec6\u80de\u6e17\u900f\u6027\u3002\u56e0\u6b64\uff0c\u4f7f\u5176\u5177\u6709\u53e3\u670d\u751f\u7269\u5229\u7528\u5ea6\u548c\u4e34\u5e8a\u6548\u679c\uff0c\u4f8b\u5982 ARV-110\u3001ARV-471 \u548c BTK PROTAC\u3002\u70b9\u51fb\u5316\u5b66\u901a\u5e38\u7528\u4e8e\u4f53\u5185\u6784\u5efaPROTAC\u5206\u5b50\uff0c\u56e0\u6b64\u9009\u62e9\u4e09\u5511\u57fa\u56e2\u6765\u8fde\u63a5POI\u548cE3\u8fde\u63a5\u9176\u914d\u4f53\u3002\u4e09\u5511\u5728\u4f53\u5185\u5f88\u96be\u4ee3\u8c22\uff0c\u56e0\u6b64\uff0c\u5f15\u5165\u4e09\u5511\u53ef\u80fd\u6709\u52a9\u4e8e\u589e\u5f3a\u4ee3\u8c22\u7a33\u5b9a\u6027\u5e76\u5ef6\u957fPROTAC\u7684\u8010\u4e45\u6027\u3002ARV-110\u7684\u53d1\u73b0\u8fc7\u7a0b\u662fPROTACs\u5f00\u53d1\u4e2d\u6781\u5177\u53c2\u8003\u4ef7\u503c\u7684\u4f8b\u5b50\u3002\u5728\u65e9\u671f\u7684\u7814\u7a76\u4e2d\uff0cAR\u62ee\u6297\u5242\u548c\u57fa\u4e8eVH032\u7684ARCC-4\u88ab\u53d1\u73b0\u5177\u6709\u6709\u6548\u7684\u964d\u89e3\u6d3b\u6027\u3002\u9274\u4e8eARCC-4\u7f3a\u4e4f\u53e3\u670d\u751f\u7269\u5229\u7528\u5ea6\uff0c\u5c06VHL\u914d\u4f53\u66ff\u6362\u4e3aCRBN\u914d\u4f53\uff0c\u5e76\u5bf9\u63a5\u5934\u8fdb\u884c\u76f8\u5e94\u4f18\u5316\u4ee5\u63d0\u9ad8\u751f\u7269\u5229\u7528\u5ea6\u3002\u7136\u540e\u5bf9\u5f39\u5934\u8fdb\u884c\u8fdb\u4e00\u6b65\u6539\u9020\uff0c\u5f97\u5230\u4e24\u79cd\u4f53\u5185\u5916\u6d3b\u6027\u5747\u4f18\u4e8eARCC-4\u7684PROTAC\uff0c\u4f46\u4e24\u79cd\u5316\u5408\u7269\u5747\u5177\u6709\u8f83\u9ad8\u7684\u6e05\u9664\u7387\u3002\u6539\u7528\u521a\u6027\u63a5\u5934\u540e\uff0c\u6d3b\u6027\u548c\u751f\u7269\u5229\u7528\u5ea6\u5f97\u5230\u6539\u5584\uff0c\u5242\u91cf\u9012\u589e\u66b4\u9732\u7684\u8fdb\u4e00\u6b65\u4f18\u5316\u6700\u7ec8\u5bfc\u81f4\u4e86 ARV-110 \u7684\u53d1\u73b0\u3002<\/p>\n

\u88685 \u5df2\u53d1\u8868\u7684 PROTAC \u7ed3\u6784\u7684 Maple \u6570\u636e\u5e93\u4e2d\u9009\u5b9a\u7684\u8fde\u63a5\u57fa\u5e8f\u7684\u51fa\u73b0\u60c5\u51b5 <\/h3>\n<\/p>\n

2. \u8fde\u63a5\u5b50\u957f\u5ea6<\/h4>\n

\u8fde\u63a5\u4f53\u7684\u957f\u5ea6\u5bf9 PROTAC \u7684\u964d\u89e3\u6d3b\u6027\u4e5f\u6709\u663e\u7740\u5f71\u54cd\u3002\u6700\u8fd1\uff0cBemis \u7b49\u63d0\u51fa\u4e86\u7ebf\u6027\u63a5\u5934\u957f\u5ea6 SAR \u7814\u7a76\u6a21\u578b\uff0c\u8868\u660e\u5177\u6709\u8f83\u957f\u63a5\u5934\u7684\u964d\u89e3\u5242\u66f4\u6709\u53ef\u80fd\u5728 PROTAC \u7684\u521d\u6b65\u8bbe\u8ba1\u4e2d\u53d6\u5f97\u6210\u529f\u3002\u4e00\u65e6\u786e\u5b9a\u4e86\u6709\u6548\u7684PROTAC\uff0c\u5c06\u9010\u6b65\u7f29\u77ed\u8fde\u63a5\u5b50\u7684\u957f\u5ea6\uff0c\u4ee5\u786e\u5b9a\u6700\u4f73\u8fde\u63a5\u5b50\u957f\u5ea6\u3002\u5f53\u63a5\u5934\u592a\u77ed\u65f6\uff0c\u7531\u4e8e\u7a7a\u95f4\u4f4d\u963b\u6548\u5e94\uff0c2\u4e2a\u914d\u4f53\u5f88\u96be\u540c\u65f6\u7ed3\u5408\u5230\u5404\u81ea\u7684\u9776\u6807\u4e0a\uff0c\u4ece\u800c\u963b\u788d\u4e86\u4e09\u5143\u590d\u5408\u7269\u7684\u5f62\u6210\u3002\u4f46\u5982\u679c\u63a5\u5934\u8fc7\u957f\uff0c\u5219\u4f1a\u963b\u788dPPI\uff0c\u5bfc\u81f4\u9776\u86cb\u767d\u6cdb\u7d20\u5316\u5931\u8d25\u3002\u6b64\u5916\uff0c\u8f83\u957f\u7684\u8fde\u63a5\u4f53\u5177\u6709\u8f83\u5927\u7684\u5206\u5b50\u91cf\uff0c\u8fd9\u4f7f\u5f97 PROTAC \u7a7f\u8fc7\u7ec6\u80de\u819c\u7684\u53ef\u80fd\u6027\u8f83\u5c0f\u3002\u56e0\u6b64\uff0c\u5c06\u521a\u6027\u8fde\u63a5\u4f53\uff08\u4f8b\u5982\u7094\u3001\u54cc\u55ea\u548c\u54cc\u5576\uff09\u63ba\u5165\u8fde\u63a5\u4f53\u4e2d\u53ef\u4ee5\u6709\u6548\u6539\u5584PROTAC\u7684\u836f\u4ee3\u52a8\u529b\u5b66\u7279\u5f81\u548c\u529f\u6548\u3002#<\/p>\n

3. \u9009\u62e9\u5408\u9002\u7684\u94fe\u63a5\u5b50\u9644\u7740\u4f4d\u70b9<\/h4>\n

PROTAC \u5177\u6709\u4e09\u4e2a\u5fc5\u8981\u7684\u7ec4\u4ef6\uff1a\u5f39\u5934\u3001E3 \u8fde\u63a5\u9176\u914d\u4f53\u548c\u8fde\u63a5\u5b83\u4eec\u7684\u8fde\u63a5\u4f53\u3002\u4e00\u65e6\u5f39\u5934\u548cE3\u8fde\u63a5\u9176\u914d\u4f53\u56fa\u5b9a\uff0c\u8fde\u63a5\u5b50\u7ec4\u6210\u3001\u957f\u5ea6\u548c\u9644\u7740\u4f4d\u70b9\u7684\u9009\u62e9\u548c\u4f18\u5316\u662f\u6784\u5efaPROTAC\u7684\u91cd\u8981\u56e0\u7d20\u3002\u5177\u6709\u5408\u9002\u8fde\u63a5\u57fa\u7684 PROTAC \u5206\u5b50\u5bf9 POI \u964d\u89e3\u7684\u6d3b\u6027\u548c\u9009\u62e9\u6027\u5177\u6709\u663e\u7740\u5f71\u54cd\u3002\u4e00\u822c\u6765\u8bf4\uff0c\u6700\u597d\u4ece\u9776\u6807\u86cb\u767d\u66b4\u9732\u4e8e\u6eb6\u5242\u7684\u4f4d\u7f6e\u8fde\u63a5\u63a5\u5934\uff0c\u8fd9\u6837\u4e0d\u4f1a\u5f71\u54cd\u5176\u914d\u4f53\u7684\u7ed3\u5408\u4eb2\u548c\u529b\u3002\u5728\u5927\u591a\u6570\u60c5\u51b5\u4e0b\uff0c\u7814\u7a76\u4eba\u5458\u5df2\u7ecf\u901a\u8fc7\u5171\u6676\u7ed3\u6784\u548cSAR\u7814\u7a76\u786e\u5b9a\u4e86\u5408\u9002\u7684\u8fde\u63a5\u4f4d\u7f6e\u3002\u5bf9\u4e8e\u5f39\u5934\u548cE3\u8fde\u63a5\u9176\u914d\u4f53\uff0c\u8fde\u63a5\u4f53\u9644\u7740\u4f4d\u70b9\u7684\u9009\u62e9\u9700\u8981\u8003\u8651\u4e0d\u5f71\u54cd\u5176\u53d7\u4f53\u539f\u6709\u7684\u4eb2\u548c\u529b\u3002\u6700\u91cd\u8981\u7684\u662f\uff0c\u4e0d\u8981\u4ece\u914d\u4f53\u7684\u5173\u952e\u6d3b\u6027\u57fa\u56e2\u884d\u751f\u8fde\u63a5\u5b50\u3002<\/p>\n

4. \u5149\u63a7\u8fde\u63a5\u5668<\/h4>\n

\u5c3d\u7ba1\u4e0e\u4f20\u7edf\u7684\u5c0f\u5206\u5b50\u6291\u5236\u5242\u76f8\u6bd4\uff0c\u50ac\u5316 MOA \u4e3a PROTAC \u5e26\u6765\u7684\u526f\u4f5c\u7528\u66f4\u5c11\u3002\u7136\u800c\uff0cPROTAC \u72ec\u7279\u7684\u50ac\u5316\u7279\u6027\u4e5f\u4e0d\u53ef\u907f\u514d\u5730\u4f1a\u56e0\u6b63\u5e38\u7ec6\u80de\u548c\u764c\u7ec6\u80de\u4e2d\u7684\u5f3a\u70c8\u964d\u89e3\u800c\u4ea7\u751f\u4e0d\u5229\u5f71\u54cd\u3002\u4e3a\u4e86\u514b\u670d\u8fd9\u4e2a\u95ee\u9898\uff0c\u5149\u63a7\u8fde\u63a5\u5668\u7684\u5f15\u5165\u4f7f\u5f97 POI \u4ee5\u65f6\u7a7a\u65b9\u5f0f\u964d\u89e3\u3002\u5c06\u5149\u53ef\u5207\u6362\u7684\u5076\u6c2e\u82ef\u57fa\u56e2\u7eb3\u5165\u8fde\u63a5\u4f53\u4e2d\u662f\u4e00\u79cd\u5229\u7528\u5149\u63a7\u5236\u964d\u89e3\u6d3b\u6027\u7684\u53ef\u9006\u65b9\u6cd5\u3002\u5728\u4e0d\u540c\u7ed9\u5b9a\u6ce2\u957f\u7684\u7167\u5c04\u4e0b\uff0cPROTAC\u4f1a\u5728\u201c\u987a\u5f0f\u201d\u548c\u201c\u53cd\u5f0f\u201d\u4e4b\u95f4\u53ef\u9006\u5730\u8f6c\u6362\uff0c\u4ece\u800c\u4ea7\u751f\u76f8\u5e94\u7684\u975e\u6d3b\u6027\u6216\u6d3b\u6027PROTAC\u7684\u6784\u8c61\u3002\u5728\u4e00\u5b9a\u6ce2\u957f\u7684\u7167\u5c04\u4e0b\uff0c\u975e\u6d3b\u6027PROTAC\u5c06\u8f6c\u5316\u4e3a\u6d3b\u6027\u4e9a\u578b\u3002\u53ea\u6709\u6d3b\u6027\u7684PROTAC\u624d\u6709\u80fd\u529b\u4e0e\u9776\u86cb\u767d\u5f62\u6210\u7a33\u5b9a\u7684\u4e09\u5143\u590d\u5408\u7269\uff0c\u5f15\u53d1\u540e\u7eed\u7684\u6cdb\u7d20\u5316\u548c\u86cb\u767d\u9176\u4f53\u964d\u89e3\u3002\u6b64\u5916\uff0c\u5728\u67d0\u4e9b\u6ce2\u957f\u7684\u5149\u4e0b\uff0c\u4e5f\u53ef\u4ee5\u901a\u8fc7\u5207\u6362\u56de\u975e\u6d3b\u6027\u5f62\u5f0f\u6765\u4e2d\u65ad\u964d\u89e3\u3002\u7814\u7a76\u4eba\u5458\u8bbe\u8ba1\u4e86\u4e00\u79cd\u53cc\u7a33\u6001 photoPROTAC\uff0c\u4f7f\u7528\u56db\u6c1f\u5076\u6c2e\u82ef\u57fa\u56e2\u6765\u5149\u5b66\u63a7\u5236 BET \u7684\u964d\u89e3\u3002photoPROTAC \u901a\u8fc7\u5149\u53ef\u5207\u6362\u56db\u6c1f\u5076\u6c2e\u82ef\u8fde\u63a5\u4f53\u5c06 VHL \u914d\u4f53\u548c JQ1 \u8fde\u63a5\u5728\u4e00\u8d77\uff08\u56fe 4a)\u3002\u6709\u7814\u7a76\u5c0f\u7ec4\u5f00\u53d1\u4e86\u4e00\u79cd\u4e0d\u540c\u7684\u65b9\u6cd5\uff0c\u901a\u8fc7\u5c06\u5149\u7b3c\u57fa\u56e2(photocaging moiety)\u63ba\u5165\u5f39\u5934\u6216 E3 \u914d\u4f53\u6765\u963b\u788d\u7a33\u5b9a POI-PROTAC-E3 \u8fde\u63a5\u9176\u590d\u5408\u7269\u7684\u5f62\u6210\uff0c\u4ece\u800c\u5149\u5b66\u63a7\u5236\u9776\u86cb\u767d\u7684\u964d\u89e3\u3002\u5728\u6307\u5b9a\u6ce2\u957f\u7684\u5149\u7167\u5c04\u4e0b\uff0c\u4e00\u65e6\u5149\u7b3c\u90e8\u5206\u88ab\u91ca\u653e\uff0c\u5b83\u5c31\u53ef\u4ee5\u6062\u590d\u5230\u6d3b\u6027\u6784\u8c61\u30022019\u5e74\uff0cPROTAC\u9996\u6b21\u4f7f\u7528\u4e86\u5149\u7b3c\u7b56\u7565\u3002\u5149\u7b3c\u90e8\u5206\u4e0e dBET1 \u4e2d\u7684\u5f39\u5934\u4fa7\u7f00\u5408\uff0c\u4ea7\u751f pcPROTAC1\uff08\u56fe 4b)\u3002\u5728365 nm\u6ce2\u957f\u7167\u5c04\u4e0b\uff0c4,5-\u4e8c\u7532\u6c27\u57fa-2-\u785d\u57fa\u82ef\u7532\u57fa\uff08DMNB\uff09\u88ab\u91ca\u653e\uff0c\u4ece\u800c\u5f62\u6210\u6d3b\u6027dBET1\u3002\u6b64\u5916\uff0c\u5149\u7b3c\u7684PROTAC-3\u5c06\u5149\u7b3c\u57fa\u56e2\u5f15\u5165CRBN\u914d\u4f53\u4fa7\u4ee5\u963b\u788dCRBN\u52df\u96c6\uff0c\u5728365 nm\u6ce2\u957f\u7167\u5c04\u4e0b\uff0c\u672a\u7b3c\u7684pcPROTAC-3\u8bf1\u5bfcBTK\u964d\u89e3\uff08\u56fe 4C\uff09\u3002\u8fd9\u4e9b\u7814\u7a76\u8bc1\u660e\u4e86\u5c06\u5149\u7b3c\u7ec4\u5f15\u5165\u4efb\u4e00\u4fa7\u7684\u53ef\u80fd\u6027\u3002\u7136\u800c\uff0c\u4e0e POI \u914d\u4f53\u7f00\u5408\u4f1a\u6bd4 E3 \u914d\u4f53\u66f4\u597d\uff0c\u56e0\u4e3a\u5b83\u6392\u9664\u4e86\u76ee\u6807\u86cb\u767d\u5728\u6ca1\u6709\u5149\u7167\u7684\u60c5\u51b5\u4e0b\u5177\u6709\u7684\u6291\u5236\u6d3b\u6027\u7684\u5f71\u54cd\u3002<\/p>\n<\/p>\n

\u56fe4 a,  photoPROTAC -1\uff0c\u5305\u542b BRD \u9776\u5411 JQ1 \u548c\u901a\u8fc7\u5149\u53ef\u5207\u6362\u56db\u6c1f\u5076\u6c2e\u82ef\u90e8\u5206\u8fde\u63a5\u7684 VHL \u914d\u4f53\u3002\u5149\u7167\u5c04\u5c06\u975e\u6d3b\u6027\u987a\u5f0f-photoPROTAC-1 \u8f6c\u5316\u4e3a\u5176\u6d3b\u6027\u53cd\u5f0f\u5f02\u6784\u4f53\uff0c\u53cd\u4e4b\u4ea6\u7136\uff0cb DMNB \u4fdd\u62a4\u7684 PROTAC \u5728 365 nm \u5904\u7167\u5c04\u4f1a\u91ca\u653e\u6709\u6548\u7684 BET \u964d\u89e3\u5242 dBET1\uff0cc\u5728 365 nm \u5904\u7167\u5c04 NVOC \u4fdd\u62a4\u7684 PROTAC \u4f1a\u91ca\u653e\u6709\u6548\u7684 BTK \u964d\u89e3\u5242\u3002<\/p>\n

5. \u53ef\u70b9\u51fb\u7684\u94fe\u63a5\u5668<\/h4>\n

\u70b9\u51fb\u53cd\u5e94\u662fPROTAC\u5728\u7ec6\u80de\u4e2d\u81ea\u7ec4\u88c5\u7684\u6709\u6548\u751f\u7269\u6b63\u4ea4\u5de5\u5177\uff0c\u5e76\u6539\u5584\u4e86PROTAC\u8f83\u5dee\u7684\u6e17\u900f\u6027\u3002Astex Pharmaceuticals \u5f00\u53d1\u4e86\u66f4\u5c0f\u7684\u57fa\u4e8e\u524d\u4f53\u7684\u7ec6\u80de\u5185 CLIPTAC\uff08\u7ec6\u80de\u5185\u70b9\u51fb\u5f62\u6210\u7684\u86cb\u767d\u6c34\u89e3\u9776\u5411\u5d4c\u5408\u4f53\uff0cCLIPTAC\uff09\u7cfb\u7edf\u3002\u8be5\u7cfb\u7edf\u4e2d\u7684\u5c0f\u5206\u5b50\u524d\u4f53\u5177\u6709\u8f83\u5c0f\u7684\u5206\u5b50\u91cf\uff0c\u4f8b\u5982\u56db\u55ea (Tz) \u6807\u8bb0\u7684\u6c99\u5229\u5ea6\u80fa\u884d\u751f\u7269 (~ 572 Da) \u548c\u53cd\u5f0f\u73af\u8f9b\u70ef (TCO) \u6807\u8bb0\u7684 JQ-1 \u884d\u751f\u7269 (~ 609 Da)\u3002Heightman\u7814\u7a76\u7ec4\u5f00\u53d1\u4e86\u4e24\u79cd CLIPTAC \u6a21\u578b\uff0c\u5b83\u4eec\u53ef\u4ee5\u901a\u8fc7\u53cd\u5f0f\u73af\u8f9b\u70ef\u548c\u56db\u55ea\u524d\u4f53\u5206\u5b50\u7684\u70b9\u51fb\u53cd\u5e94\u5728\u7ec6\u80de\u5185\u5408\u6210\u3002\u7ed3\u679c\u8868\u660e\uff0cCLIPTACs\u80fd\u591f\u6210\u529f\u8bf1\u5bfcHeLa\u3001A375\u548cHCT116\u7b49\u4e09\u79cd\u7ec6\u80de\u7cfb\u4e2dBRD4\u548cERK1\/2\uff08\u7ec6\u80de\u5916\u8c03\u8282\u86cb\u767d\u6fc0\u9176\uff09\u7684\u964d\u89e3\u3002\u8fd9\u4e00\u5f00\u521b\u6027\u7684\u7b56\u7565\u4e0d\u4ec5\u63d0\u9ad8\u4e86PROTAC\u7684\u7ec6\u80de\u901a\u900f\u6027\u548c\u6eb6\u89e3\u5ea6\uff0c\u800c\u4e14\u65e0\u9700\u8fdb\u884c\u8fde\u63a5\u5b50\u4f18\u5316\uff0c\u5bf9\u4e8e\u4e0d\u540c\u7684\u76ee\u6807\u86cb\u767d\u964d\u89e3\u53ea\u9700\u6539\u53d8\u86cb\u767d\u914d\u4f53\u90e8\u5206\uff0c\u66f4\u52a0\u7075\u6d3b\u65b9\u4fbf\u3002<\/p>\n

4.3 \u8ba1\u7b97\u673a\u4eff\u771f\u52a0\u901f PROTAC \u8bbe\u8ba1<\/h3>\n

PROTACs\u7684\u5408\u7406\u8bbe\u8ba1\u5305\u62ec\u4e09\u4e2a\u7ec4\u6210\u90e8\u5206\uff1a\u5f39\u5934\u3001E3\u914d\u4f53\u548c\u8fde\u63a5\u4f53\u3002\u867d\u7136\u5f39\u5934\u548cE3\u914d\u4f53\u7684\u53d1\u73b0\u8fc7\u7a0b\u672c\u8d28\u4e0a\u4e0e\u5c0f\u5206\u5b50\u76f8\u4f3c\uff0c\u4f46\u8fde\u63a5\u4f53\u7684\u8bbe\u8ba1\u6709\u4e9b\u6311\u6218\u6027\uff0c\u56e0\u4e3aPOI\u548cE3\u8fde\u63a5\u9176\u5728\u6ca1\u6709\u6709\u6548PROTAC\u7684\u60c5\u51b5\u4e0b\u65e0\u6cd5\u76f8\u4e92\u4f5c\u7528\u3002\u968f\u7740\u4eba\u4eec\u66f4\u597d\u5730\u7406\u89e3\u8fde\u63a5\u5b50\u5bf9 PROTAC \u7684\u7406\u5316\u6027\u8d28\u548c\u964d\u89e3\u6d3b\u6027\u7684\u91cd\u8981\u6027\uff0c\u5f53\u524d\u7684\u7814\u7a76\u96c6\u4e2d\u5728\u4ece\u5934 PROTAC \u8bbe\u8ba1\u4e0a\u3002\u8fde\u63a5\u5b50\u7684\u957f\u5ea6\u3001\u7ec4\u6210\u3001\u7075\u6d3b\u6027\u548c\u8fde\u63a5\u4f4d\u70b9\u90fd\u5bf9\u964d\u89e3\u6548\u7387\u4ea7\u751f\u5de8\u5927\u5f71\u54cd\u3002\u6b64\u5916\uff0c\u53e6\u4e00\u4e2a\u8bbe\u8ba1\u6311\u6218\u6765\u81ea\u4e8ePROTAC\u5206\u5b50\u5f80\u5f80\u6eb6\u89e3\u6027\u5dee\u3001\u6e17\u900f\u6027\u5dee\u3001\u751f\u7269\u5229\u7528\u5ea6\u4f4e\u548c\u4e0d\u53ef\u9884\u6d4b\u7684\u94a9\u72b6\u6548\u5e94\uff0c\u8fd9\u963b\u788d\u4e86PROTAC\u7684\u4e34\u5e8a\u8f6c\u5316\u3002\u56e0\u6b64\uff0c\u8feb\u5207\u9700\u8981\u5bfb\u627e\u65b0\u7684\u65b9\u6cd5\u6765\u63d0\u9ad8PROTAC\u7684\u53d1\u73b0\u6548\u7387\u3002\u4e3a\u4e86\u52a0\u901f\u5408\u7406 PROTAC \u7684\u8bbe\u8ba1\u8fdb\u5ea6\u3002Zheng \u7b49\u4eba\u521b\u5efa\u4e86\u4e00\u79cd\u65b0\u9896\u7684\u6df1\u5ea6\u751f\u6210\u6a21\u578b\uff08PROTAC-RL\uff09\u3002\u5c06\u4e00\u5bf9E3\u914d\u4f53\u548c\u5f39\u5934\u8f93\u5165\u5230\u6a21\u578b\u4e2d\uff0c\u5728\u5f3a\u5316\u5b66\u4e60\uff08RL\uff0cReinforcement Learning\uff09\u7684\u6307\u5bfc\u4e0b\uff0c\u8f93\u51fa\u8bbe\u8ba1\u7684\u63a5\u5934\u4ee5\u53ca\u5177\u6709\u7279\u5b9a\u6027\u8d28\u7684\u5316\u5b66\u4e0a\u53ef\u884c\u7684PROTAC\u3002\u5177\u4f53\u6765\u8bf4\uff0c\u4ed6\u4eec\u9996\u5148\u9884\u8bad\u7ec3\u4e86\u4e00\u4e2a\u57fa\u4e8etransformer\u795e\u7ecf\u7f51\u7edc\u7684\u94fe\u63a5\u5b50\u751f\u6210\u6a21\u578b\uff08Proformer\uff09\u3002\u4e3a\u4e86\u514b\u670dPROTAC\u8bad\u7ec3\u6570\u636e\u91cf\u4f4e\u7684\u6311\u6218\uff0c\u9996\u5148\u901a\u8fc7\u8bb8\u591a\u4e0ePROTAC\u5927\u5c0f\u76f8\u4f3c\u7684\u51c6PROTAC\u5c0f\u5206\u5b50\u5bf9\u6a21\u578b\u8fdb\u884c\u9884\u8bad\u7ec3\uff0c\u7136\u540e\u7528\u771f\u5b9e\u7684PROTAC\u96c6\u548c\u589e\u5f3a\u6570\u636e\u5bf9\u6a21\u578b\u8fdb\u884c\u5fae\u8c03\u3002Proformer \u968f\u540e\u88ab\u8f93\u5165\u57fa\u4e8e\u8bb0\u5fc6\u7684\u5f3a\u5316\u5b66\u4e60\u6846\u67b6 PROTAC-RL\uff0c\u5e76\u83b7\u5f97\u7ecf\u9a8c\u5956\u52b1\u4ee5\u83b7\u5f97\u5177\u6709\u7406\u60f3 PK \u5c5e\u6027\u7684 PROTAC\u3002\u4e3a\u4e86\u8bc1\u660e\u6709\u6548\u6027\uff0c\u7814\u7a76\u56e2\u961f\u5c06BRD4\u8bc6\u522b\u4e3aPOI\u5e76\u751f\u6210\u4e865000\u4e2aPROTAC\u3002\u4f9d\u9760\u8d85\u7ea7\u8ba1\u7b97\u80fd\u529b\uff0c\u4ed6\u4eec\u8fdb\u4e00\u6b65\u5bf9\u8fd9\u4e9b\u865a\u62df\u5206\u5b50\u8fdb\u884c\u805a\u7c7b\u548c\u7b5b\u9009\u3002\u7814\u7a76\u4eba\u5458\u6700\u7ec8\u9009\u62e9\u3001\u5408\u6210\u5e76\u5b9e\u9a8c\u6d4b\u8bd5\u4e86\u516d\u79cdPROTAC\uff0c\u5176\u4e2d\u4e09\u79cd\u8868\u73b0\u51fa\u6291\u5236\u6d3b\u6027\uff0c\u4e00\u79cd\u5148\u5bfc\u5316\u5408\u7269\u8868\u73b0\u51fa\u9488\u5bf9\u80bf\u7624\u7ec6\u80de\u7cfb\u7684\u9ad8\u6297\u589e\u6b96\u6d3b\u6027\u548c\u826f\u597d\u7684\u836f\u4ee3\u52a8\u529b\u5b66\u3002Western blot \u68c0\u6d4b\u7ed3\u679c\u663e\u793a\u5316\u5408\u7269 1-3\uff08\u56fe 2j) \u4f4e\u5fae\u6469\u5c14\u6d53\u5ea6\u964d\u89e3\u7ec6\u80de\u5185 BRD4\u3002\u6240\u6709\u8fd9\u4e9b\u5316\u5408\u7269\u5728\u5fae\u6469\u5c14\u6d53\u5ea6\u4e0b\u5747\u8868\u73b0\u51fa\u9488\u5bf9 Molt4 \u7ec6\u80de\u7cfb\u7684\u6297\u589e\u6b96\u6d3b\u6027\u3002\u6574\u4e2a\u7814\u7a76\u5de5\u4f5c\u4ec5\u8017\u65f649\u5929\uff0c\u8868\u660e\u8ba1\u7b97\u673a\u6a21\u578b\u7684\u5e94\u7528\u53ef\u4ee5\u4fc3\u8fdb\u9ad8\u6548\u5408\u7406\u7684PROTAC\u8bbe\u8ba1\u548c\u4f18\u5316\u3002<\/p>\n

5. PROTACs\u5728\u75be\u75c5\u4e2d\u7684\u5e94\u7528<\/p>\n

<\/h2>\n

\u5728\u8fc7\u53bb\u7684\u4e8c\u5341\u5e74\u4e2d\uff0cPROTAC \u5728\u89e3\u51b3\u75be\u75c5\u76f8\u5173\u86cb\u767d\u65b9\u9762\u8868\u73b0\u51fa\u4e86\u72ec\u7279\u7684\u4f18\u52bf\u3002\u76ee\u524d\uff0c\u4e00\u4e9b\u5177\u6709\u4ee3\u8868\u6027\u7684PROTAC\u5df2\u8fdb\u5165\u6cbb\u7597\u764c\u75c7\u7684\u4e34\u5e8a\u8bd5\u9a8c\u3002\u9664\u4e86\u764c\u75c7\u4e4b\u5916\uff0cPROTACs\u5728\u6cbb\u7597\u5176\u4ed6\u75be\u75c5\u65b9\u9762\u4e5f\u5177\u6709\u5de8\u5927\u4f18\u52bf\uff0c\u4f8b\u5982\u795e\u7ecf\u9000\u884c\u6027\u75be\u75c5\u3001\u514d\u75ab\u7cfb\u7edf\u75be\u75c5\u6216\u75c5\u6bd2\u611f\u67d3\u3002\u5728\u8fd9\u91cc\uff0c\u6211\u4eec\u603b\u7ed3\u4e86\u8fd9\u4e9b\u75be\u75c5\u7684\u4e00\u4e9b PROTAC \u9776\u6807\uff08\u8868 6\uff09\u3002<\/p>\n

\u88686 \u9488\u5bf9\u4e0d\u540c\u75be\u75c5\u7684\u591a\u79cd PROTAC<\/h3>\n

\u75be\u75c5\u9886\u57df\u76ee\u6807\u764c\u75c7<\/p>\n","protected":false},"excerpt":{"rendered":"

\u8fd1\u5e74\u6765\uff0c\u86cb\u767d\u6c34\u89e3\u9776\u5411\u5d4c\u5408\u4f53\uff08PROTAC\uff09\u6280\u672f\u5df2\u6210\u4e3a\u4e00\u79cd\u65b0\u578b\u6cbb\u7597\u8303\u4f8b\u3002PROTA … \u7ee7\u7eed\u9605\u8bfb →<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[70],"tags":[],"class_list":["post-45792","post","type-post","status-publish","format-standard","hentry","category-70"],"_links":{"self":[{"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=\/wp\/v2\/posts\/45792","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=45792"}],"version-history":[{"count":0,"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=\/wp\/v2\/posts\/45792\/revisions"}],"wp:attachment":[{"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=45792"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=45792"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/zydq.1006ss.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=45792"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}