Optimization of PROTAC Ternary Complex Using DNA Encoded Library Approach

The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a heterobifunctional degrader forms a ternary complex with a target protein of interest (POI) and an E3 ligase, which results in ubiquitination and...

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Bibliographic Details
Published in:	ACS chemical biology Vol. 18; no. 1; pp. 25 - 33
Main Authors:	Chen, Qiuxia, Liu, Chuan, Wang, Wei, Meng, Xiaoyun, Cheng, Xuemin, Li, Xianyang, Cai, Longying, Luo, Linfu, He, Xu, Qu, Huan, Luo, Jing, Wei, Hong, Gao, Sen, Liu, Guansai, Wan, Jinqiao, Israel, David I., Li, Jin, Dou, Dengfeng
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 20-01-2023
Subjects:	Nuclear Proteins - metabolism Proteolysis Transcription Factors - metabolism Ubiquitin-Protein Ligases - metabolism Ubiquitination
Online Access:	Get full text
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Summary:	The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a heterobifunctional degrader forms a ternary complex with a target protein of interest (POI) and an E3 ligase, which results in ubiquitination and proteasomal degradation of the POI. While ternary complex formation is a key attribute of PROTAC degraders, modification of the PROTAC molecule to optimize ternary complex formation and protein degradation can be a labor-intensive and tedious process. In this study, we take advantage of DNA-encoded library (DEL) technology to efficiently synthesize a vast number of possible PROTAC molecules and describe a parallel screening approach that utilizes DNA barcodes as reporters of ternary complex formation and cooperative binding. We use a designed PROTAC DEL against BRD4 and CRBN to describe a dual protein affinity selection method and the direct discovery of novel, potent BRD4 PROTACs that importantly demonstrate clear SAR. Such an approach evaluates all the potential PROTACs simultaneously, avoids the interference of PROTAC solubility and permeability, and uses POI and E3 ligase proteins in an efficient manner.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1554-8929 1554-8937 1554-8937
DOI:	10.1021/acschembio.2c00797