Selective degradation-inducing probes for studying cereblon (CRBN) biology

被引：16

作者：

Powell, Chelsea E. ^{[1
,2
]}

Du, Guangyan ^{[1
,2
]}

Bushman, Jonathan W. ^{[1
,2
]}

He, Zhixiang ^{[1
,2
]}

Zhang, Tinghu ^{[1
,2
]}

Fischer, Eric S. ^{[1
,2
]}

Gray, Nathanael S. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

来源：

RSC MEDICINAL CHEMISTRY | 2021年 / 12卷 / 08期

基金：

美国国家卫生研究院;

关键词：

LENALIDOMIDE; IKAROS; TARGET; GENE;

D O I：

10.1039/d0md00382d

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1381 / 1390

页数：10

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