Thalidomide, originally developed as a sedative drug, causes multiple defects due to severe teratogenicity, but it has been re-purposed for treating multiple myeloma, and derivatives such as lenalidomide and pomalidomide have been developed for treating blood cancers. Although the molecular mechanisms of thalidomide and its derivatives remained poorly understood until recently, we identified cereblon (CRBN), a primary direct target of thalidomide, using ferrite glycidyl methacrylate (FG) beads. CRBN is a ligand-dependent substrate receptor of the E3 ubiquitin ligase complex cullin-RING ligase 4 (CRL4CRBN). When a ligand such as thalidomide binds to CRBN, it recognizes various 'neosubstrates' depending on the shape of the ligand. CRL4CRBN binds many neosubstrates in the presence of various ligands. CRBN has been utilized in a novel protein knockdown technology named proteolysis targeting chimeras (PROTACs). Heterobifunctional molecules such as dBET1 are being developed to specifically degrade proteins of interest. Herein, we review recent advances in CRBN research.

中文翻译：

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沙利度胺及其衍生物的分子机理。

沙利度胺最初是作为镇静药开发的，由于严重的致畸性会引起多种缺陷，但已被重新用于治疗多发性骨髓瘤，并开发了来那度胺和泊马利度胺等衍生物治疗血液癌。尽管直到最近仍不清楚沙利度胺及其衍生物的分子机制，但我们使用铁氧体甲基丙烯酸缩水甘油酯（FG）珠粒鉴定了塞利度胺的主要直接靶标塞波隆（CRBN）。CRBN是E3泛素连接酶复合物cullin-RING连接酶4（CRL4CRBN）的依赖配体的底物受体。当沙利度胺等配体与CRBN结合时，它会根据配体的形状识别出各种“新底物”。在存在各种配体的情况下，CRL4CRBN结合许多新底物。CRBN已用于一种新型的蛋白敲低技术，称为蛋白水解靶向嵌合体（PROTAC）。正在开发异双功能分子（例如dBET1）以特异性降解目标蛋白质。本文中，我们回顾了CRBN研究的最新进展。