Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC
Jiexuan Chen, Mingfei Wu, Jun Mo, Ju-Eun Hong, Wei Wang, Yuheng Jin, Xinfei Mao, Xiang Liao, Kailin Li, Xiaoli Yu, Sikang Chen, Shenxin Zeng, Wenhai Huang, Hongxia Xu, Jian Wu, Ji Cao, Yubo Zhou, Meidan Ying, Cheng‐Liang Zhu, Qiaojun He, Bo Zhang, Nengming Lin, Xiaowu Dong, Jinxin Che
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.