泛素连接酶
溴尿嘧啶
泛素
RNF4型
蛋白质降解
DNA连接酶
BRD4
DDB1型
泛素蛋白连接酶类
化学
蛋白酶体
药物发现
生物化学
可药性
计算生物学
锌指
生物
转录因子
组蛋白
DNA
基因
作者
Carl C. Ward,Jordan I. Kleinman,Scott M. Brittain,Patrick S. Lee,Clive Yik‐Sham Chung,Kenneth Kim,Yana Petri,Jason R. Thomas,John A. Tallarico,Jeffrey M. McKenna,Markus Schirle,Daniel K. Nomura
标识
DOI:10.1021/acschembio.8b01083
摘要
Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only a few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications.
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