Triazine-Based Covalent DNA-Encoded Libraries for Discovery of Covalent Inhibitors of Target Proteins

作者：Linjie Li, Mingbo Su, Weiwei Lu, Hongzhi Song, Jiaxiang Liu, Xin Wen, Yanrui Suo, Jingjing Qi, Xiaomin Luo, Yubo Zhou, Xin-Hua Liao, Jia Li, Xiaojie Lu · 发表于：ACS Medicinal Chemistry Letters · 年份：2022 · DOI：10.1021/acsmedchemlett.2c00127 · 被引用次数：47 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Chronic Lymphocytic Leukemia Research、Adenosine and Purinergic Signaling

Since ibrutinib was approved by the FDA as an effective monotherapy for chronic lymphocytic leukemia (CLL) and multilymphoma, more and more FDA-approved covalent drugs are coming back into the market. On this occasion, the resurgence of interest in covalent drugs calls for more hit discovery techniques. However, the limited numbers of covalent libraries prevent the development of this area. Herein, we report the design of covalent DNA-encoded library (DEL) and its selection method for the discovery of covalent inhibitors for target proteins. These triazine-based covalent DELs yielded potent compounds after covalent selection against target proteins, including Bruton's Tyrosine Kinase (BTK), Janus kinase 3 (JAK3), and peptidyl-prolyl cis/trans isomerase NIMA-interacting-1 (Pin1).