Background Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex, including cullin 4A, DNA damage binding protein 1, and regulator of cullin 1. CC-220 binds to cereblon, affecting the ubiquitin E3 ligase activity and mediating antiproliferative and immunomodulatory effects on lymphocytes...
近年来,CRL4CRBN复合物和其他E3连接酶被广泛探索为通过异双功能小分子降解典型的“不可成药”蛋白的靶点,称为蛋白水解靶向嵌合体(PROTACs)。 本文主要介绍了在多发性骨髓瘤未来的治疗方法中,以CRBN依赖的方式调节CRL4CRBNE3连接酶活性的方法。 图1.CRL4CRBNE3连...
因此,IMIDs通常被认为是PROTAC“分子胶”部分的先驱,因为它们促进了CRBN与许多治疗相关的新底物的相互作用的发现。 2015年开发了第一个基于CRBN的靶向降解BRD4的PROTAC,以沙利度胺为CRBN E3泛素连接酶配体和溴结构域作为靶向蛋白。结果表明,DBET1在MM和AML细胞系中诱导高选择性的CRBN依赖性BET蛋白降解。基于CRL4 CR...
近年来,CRL4CRBN复合物和其他E3连接酶被广泛探索为通过异双功能小分子降解典型的“不可成药”蛋白的靶点,称为蛋白水解靶向嵌合体(PROTACs)。 本文主要介绍了在多发性骨髓瘤未来的治疗方法中,以CRBN依赖的方式调节CRL4CRBN E3连接酶活性的方法。 ▲图1.CRL4CRBN E3连接酶复合物泛素化研究进展 2 免疫调节药物(IMiDs...
A Cul4 E3 ubiquitin ligase regulates histone hand-off during nucleosome assembly. Cell. 2013;155:817–29. Article CAS PubMed PubMed Central Google Scholar Liu J, Ye J, Zou X, Xu Z, Feng Y, Zou X, et al. CRL4A(CRBN) E3 ubiquitin ligase restricts BK channel activity and prevents ...
Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of haematologic malignancies. It was shown that IMiDs impart gain-of-function properties to the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase that enable bin
Lenalidomide mediates the ubiquitination and degradation of Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and casein kinase 1α (CK1α) by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4CRBN E3 ubiquitin ligase. Through this mechanism, lenalidomide ...
Targeting the CRL4CRBN E3 ubiquitin ligase with CC-220 resulted in a potent reduction in Aiolos and Ikaros protein levels in B cells, T cells, and monocytes, and inhibited autoantibody production. Administration of single doses of CC-220 (0.3-6 mg) reduced intracellular Aiolos protein ...
目前,大多数PROTACs使用CRL4CRBN和VHL两种E3泛素连接酶作为招募连接酶。因此,IMIDs通常被认为是PROTAC“分子胶”部分的先驱,因为它们促进了CRBN与许多治疗相关的新底物的相互作用的发现。 2015年开发了第一个基于CRBN的靶向降解BRD4的PROTAC,以沙利度胺为CRBN E3泛...
While the more recent discovery of the CRL4CRBN ubiquitin ligase as a primary cellular target of thalidomide has been a milestone in understanding thalidomide teratogenicity, a detailed molecular understanding of thalidomide action remains to be elucidated. In the second part of my thesis, I provide...