Selective degradation-inducing probes for studying cereblon (CRBN) biology,RSC Medicinal Chemistry

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Selective degradation-inducing probes for studying cereblon (CRBN) biology
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-07-06 , DOI: 10.1039/d0md00382d
Chelsea E Powell _{1,

2} , Guangyan Du _{1,

2} , Jonathan W Bushman _{1,

2} , Zhixiang He _{1,

2} , Tinghu Zhang _{1,

2} , Eric S Fischer _{1,

2} , Nathanael S Gray _{1,

2}

Affiliation

Targeted protein degradation represents a rapidly growing area in drug discovery and development. Moreover, small molecules that induce the targeted degradation of a given protein also represent an important addition to the chemical probes toolbox as these compounds can achieve selective protein knockdown, thus providing an approach that is orthogonal to genetic knockdowns. In order to develop degradation-inducing chemical probes for studying cereblon (CRBN) biology, we generated six CRBN–CRBN (homo-PROTAC) degraders and six CRBN–VHL (hetero-PROTAC) degraders. From these compounds we identified two potent and selective CRBN degraders (ZXH-4-130 and ZXH-4-137), both of which are CRBN–VHL compounds. We characterized these lead degraders by quantitative proteomics in five cell lines (MM1.S, Kelly, SK-N-DZ, HEK293T, and MOLT-4) and observed high selectivity for CRBN in all cell lines. Furthermore, we directly compared our compounds to current lead CRBN degraders and demonstrated how these probes can be used as chemical knockdown reagents for studying CRBN-dependent processes. Overall, our work provides a roadmap for thorough degrader characterization by combination western and proteomic analysis, as illustrated by the identification of ZXH-4-130 and ZXH-4-137 as CRBN-knockdown tool compounds suitable for cell-based studies.

中文翻译：

用于研究 cereblon (CRBN) 生物学的选择性降解诱导探针

靶向蛋白质降解代表了药物发现和开发中快速增长的领域。此外，诱导给定蛋白质靶向降解的小分子也代表了化学探针工具箱的重要补充，因为这些化合物可以实现选择性蛋白质敲低，从而提供了一种与基因敲低正交的方法。为了开发用于研究 cereblon (CRBN) 生物学的降解诱导化学探针，我们生成了 6 个 CRBN-CRBN (homo-PROTAC) 降解剂和 6 个 CRBN-VHL (hetero-PROTAC) 降解剂。从这些化合物中，我们鉴定出了两种有效且选择性的 CRBN 降解剂（ZXH-4-130和ZXH-4-137），它们都是 CRBN-VHL 化合物。我们通过定量蛋白质组学在五种细胞系（MM1.S、Kelly、SK-N-DZ、HEK293T 和 MOLT-4）中对这些先导降解剂进行了表征，并观察到所有细胞系对 CRBN 的高选择性。此外，我们直接将我们的化合物与当前领先的 CRBN 降解剂进行比较，并演示了如何将这些探针用作化学敲低试剂来研究 CRBN 依赖性过程。总体而言，我们的工作为通过结合蛋白质组学分析来彻底表征降解剂提供了路线图，如将ZXH-4-130和ZXH-4-137鉴定为适合基于细胞的研究的 CRBN 敲低工具化合物所说明的那样。

更新日期：2021-07-06

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