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CRL4CRBN-聚马立度胺相互作用的下一代PROTACs也针对BET蛋白(ARV825),...
Lenalidomide (CC-5013) 是一种泛素 E3 连接酶 cereblon (CRBN) 的配体,可通过 CRBN-CRL4 泛素连接酶对两种淋巴转录因子 IKZF1 和 IKZF3 进行选择性泛素化和降解。Lenalidomide (CC-5013) 特别地抑制成熟 B 细胞淋巴瘤 (包括多发性骨髓瘤) 的生长,并诱导 T 细胞释放白细胞介素-2 (IL-2)。 生物活性:来...
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In the case of cereblon two avenues exist; either heterobifunctional PROTACs, or discrete cereblon ligands that induce a specific neosubstrate degron association to the complex. Here we present a degron blocking approach, whereby structural and in silico understandings of degron association has ...
过程过早地在第419个氨基酸的位置引入一个终止密码子,从而产生CRBN R419X这一突变体.这种无义突变会导致儿童精神发育迟滞的发生.然而,对CRBN突变引发精神发育迟滞的详细分子机制,一直以来都不清楚.前人的研究已经证实该蛋白质能与DDB1,ROC1,Cullin4A形成一个Cullin RING E3 Ligase,即CRL4-CRBN泛素连接酶.本课题...
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
We demonstrated that loss of UBE2M or members of the constitutive photomorphogenesis 9 (COP9) signalosome results in altered neddylation of cullin 4A and impairs lenalidomide-dependent CRL4CRBN activity. Additionally, we established that UBE2D3 and UBE2G1 play distinct roles in substrate ...
产品活性:Golcadomide (CC-99282) 是一种有效的且具有口服活性的 CRBN E3 连接酶 调节剂 (CELMoD)。Golcadomide 与 CRL4 CRBN E3 泛素连接酶底物受体 CRBN 相互作用,诱导转录因子 Ikaros 和 Aiolos 的招募和泛素介导的蛋白酶体降解。Golcadomide 有望用于慢性淋巴细胞白血病 (CLL) 和非霍奇金淋巴瘤 (NHL) ...
Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1. Wei LiuAmerican Chemical SocietyHansen JD, Condroski K, Correa M, Muller G, Man HW, et al. (2017) Protein Degradation ...
H. Thoma, Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase. Nature 532, 127-130 (2016). doi:10.1038/nature16979 MedlinePetzold, G., Fischer, E.S., and Thoma€, N.H. (2016). Structural basis of lenalido- mide-induced CK1a degradation by ...