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Chemical Ligand Space of Cereblon
ACS Omega ( IF 4.1 ) Pub Date : 2018-09-14 00:00:00 , DOI: 10.1021/acsomega.8b00959
Iuliia Boichenko 1 , Kerstin Bär 1 , Silvia Deiss 1 , Christopher Heim 1 , Reinhard Albrecht 1 , Andrei N. Lupas 1 , Birte Hernandez Alvarez 1 , Marcus D. Hartmann 1
Affiliation  

The protein cereblon serves as a substrate receptor of a ubiquitin ligase complex that can be tuned toward different target proteins by cereblon-binding agents. This approach to targeted protein degradation is exploited in different clinical settings and has sparked the development of a growing number of thalidomide derivatives. Here, we probe the chemical space of cereblon binding beyond such derivatives and work out a simple set of chemical requirements, delineating the metaclass of cereblon effectors. We report co-crystal structures for a diverse set of compounds, including commonly used pharmaceuticals, but also find that already minimalistic cereblon-binding moieties might exert teratogenic effects in zebrafish. Our results may guide the design of a post-thalidomide generation of therapeutic cereblon effectors and provide a framework for the circumvention of unintended cereblon binding by negative design for future pharmaceuticals.

中文翻译:

赛百隆的化学配体空间

大脑蛋白可作为泛素连接酶复合物的底物受体,可以通过大脑蛋白结合剂针对不同的目标蛋白进行调节。这种靶向蛋白质降解的方法已在不同的临床环境中得到应用,并引发了越来越多的沙利度胺衍生物的开发。在这里,我们探讨了除此类衍生物之外的大脑神经元结合的化学空间,并得出了一组简单的化学要求,描绘了大脑神经元效应子的亚类。我们报道了包括常用药物在内的各种化合物的共晶体结构,但同时也发现已经极简的脑神经结合部分可能在斑马鱼中产生致畸作用。
更新日期:2018-09-14
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