Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-01-04 DOI:10.1021/acs.jmedchem.4c02438

Jiexuan Chen, Mingfei Wu, Jun Mo, Ju Hong, Wei Wang, Yuheng Jin, Xinfei Mao, Xueyan Liao, Kailin Li, Xiaoli Yu, Sikang Chen, Shenxin Zeng, Wenhai Huang, Hongxia Xu, Jian Wu, Ji Cao, Yubo Zhou, Meidan Ying, Chengliang Zhu, Qiaojun He, Bo Zhang, Nengming Lin, Xiaowu Dong, Jinxin Che

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Abstract

The tedious synthesis and limited throughput biological evaluation remain a great challenge for discovering new proteolysis targeting chimera (PROTAC). To rapidly identify potential PROTAC lead compounds, we report a platform named Auto-RapTAC. Based on the modular characteristic of the PROTAC molecule, a streamlined workflow that integrates lab automation with “click chemistry” joint building-block libraries was constructed. This facilitates the autonomous generation of a variety of PROTACs, each with distinct linkers and E3 ligase ligands, all stored in biocompatible solutions. The ready-for-screening (R4S) approach, when paired with fluorescence-based assays, enables the efficient assessment of the PROTAC degradation activity in a high-throughput manner. To further test the capability of the platform, we identify six new PROTACs that target CDK2, CDK12, and BCL6 within a mere 8-day time frame for each target. In all, this platform could find broad application not only in discovering new PROTACs but also in the rapid development of novel heterobifunctional modalities.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.