用于发现靶蛋白共价抑制剂的基于三嗪的共价DNA编码文库
Triazine-Based Covalent DNA-Encoded Libraries for Discovery of Covalent Inhibitors of Target Proteins.
作者信息
Li Linjie, Su Mingbo, Lu Weiwei, Song Hongzhi, Liu Jiaxiang, Wen Xin, Suo Yanrui, Qi Jingjing, Luo Xiaomin, Zhou Yu-Bo, Liao Xin-Hua, Li Jia, Lu Xiaojie
机构信息
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
出版信息
ACS Med Chem Lett. 2022 Aug 15;13(10):1574-1581. doi: 10.1021/acsmedchemlett.2c00127. eCollection 2022 Oct 13.
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).
自从依鲁替尼被美国食品药品监督管理局（FDA）批准作为慢性淋巴细胞白血病（CLL）和多种淋巴瘤的有效单药疗法以来，越来越多经FDA批准的共价药物重新进入市场。在这种情况下，对共价药物兴趣的复苏需要更多的命中发现技术。然而，共价文库数量有限阻碍了该领域的发展。在此，我们报告了共价DNA编码文库（DEL）的设计及其用于发现靶蛋白共价抑制剂的筛选方法。这些基于三嗪的共价DEL在针对靶蛋白进行共价筛选后产生了强效化合物，包括布鲁顿酪氨酸激酶（BTK）、Janus激酶3（JAK3）和肽基脯氨酰顺/反异构酶NIMA相互作用蛋白1（Pin1）。
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