沙利度胺,泊马度胺和来那度胺,统称为免疫调节酰亚胺药物(IMiDs),经常在蛋白水解靶向嵌合体(PROTACs)中用作cereblon(CRBN)E3连接酶募集配体。然而,它们的分子胶特性共同选择CRL4CRBN降解其非天然底物可能导致基于IMiD的PROTAC降解剂的不期望的脱靶效应。在这里,我们报道了一个小文库的有效和细胞可渗透的CRBN配体,通过基于结构的设计,对IMiD的众所周知的CRBN新衬底具有高选择性。它们被进一步用于构建含溴结构域的蛋白4(BRD4)降解物,这成功地耗尽了测试细胞中的BRD4。总的来说,我们报告了一系列功能化的CRBN招聘人员,这些招聘人员规避了传统IMiD的滥交,这项研究为许多其他治疗靶标的选择性CRBN招募PROTACs的开发提供了信息。
Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (
CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable
CRBN ligands, which exert high selectivity over the well-known
CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized
CRBN recruiters that circumvent the promiscuity from traditional IMiDs, and this study is informative to the development of selective
CRBN-recruiting PROTACs for many other therapeutic targets.