Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α.

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Breanna L Zerfas, Yingpeng Liu, Jianwei Che, Katherine A Donovan, John M Hatcher, Fidel Huerta, Rebecca J Metivier, Radosław P Nowak, Leah Ragosta, Tiffany Tsang, Eric S Fischer, Lyn H Jones
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引用次数: 0

Abstract

IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or kinase domains of the enzyme have limited utility and targeted degradation would address additional scaffolding functions of the protein. Here, we describe the design and development of IRE1α proteolysis targeting chimeras (PROTACs) based on a lysine-reactive salicylaldehyde RNase inhibitor, and present the structure-activity relationships (SARs) that delivered the first highly selective degraders of a native ER-membrane associated protein. Medicinal chemistry optimization exploited ternary complex computational modelling to inform design, HiBiT-SpyTag IRE1α degradation and NanoBRET cereblon occupancy cell-based assays to generate SARs, and mass spectrometry-based proteomics to assess broad selectivity in an unbiased manner. Merging IRE1α and CRBN ligand chemotypes provided the truncated chimera CPD-2828 with physicochemical properties more akin to an oral molecular glue degrader than a traditional PROTAC.

截断型IRE1α异二价化学探针降解物的结构导向设计。
IRE1α是一种参与未折叠蛋白反应(UPR)的内质网蛋白,内质网应激途径的失调与多种疾病有关。胞质内切酶或酶激酶结构域的抑制剂效用有限,靶向降解将解决蛋白质的额外支架功能。在这里,我们描述了基于赖氨酸反应性水杨醛RNase抑制剂的IRE1α蛋白水解靶向嵌合体(PROTACs)的设计和开发,并介绍了结构-活性关系(SARs),该结构-活性关系提供了天然er膜相关蛋白的第一个高选择性降解物。药物化学优化利用三重复杂计算模型为设计提供信息,利用HiBiT-SpyTag IRE1α降解和NanoBRET小脑占用细胞分析生成sar,利用基于质谱的蛋白质组学以无偏的方式评估广泛的选择性。合并IRE1α和CRBN配体的化学型使截断嵌合体CPD-2828的物理化学性质更类似于口服分子胶降解剂,而不是传统的PROTAC。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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