Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1
Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1
复制标题
DOI：
10.1021/acs.jmedchem.6b01911
复制
发表时间：
2018-01-25
影响因子：
7.3
通讯作者：
Lu, Chin-Chun
中科院分区：
文献类型：
--
作者：
Hansen, Joshua D.;Condroski, Kevin;Lu, Chin-Chun
我们先前披露了脑调节剂3（CC-885）的鉴定，其有效的抗肿瘤活性是通过GSPT1的降解而介导的。我们在此描述了3个类似物的结构活性关系，并探索了与结构相关的二氨基丁氨酸类别的探索。观察到的蛋白质降解活性可以部分通过对接到先前披露的3-CRBN-GSPT1共晶三元复合物中。对于SAP。通过共晶体综合体无法合理化，我们试图通过内部开发的QSAR模型来预测SAR。通过这些分析，可以在感兴趣的两种蛋白质，GSPT1和Aiolos之间实现选择性蛋白质降解。
We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAP. that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.