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

Linjie Li; Mingbo Su; Weiwei Lu; Hongzhi Song; Jiaxiang Liu; Xin Wen; Yanrui Suo; Jingjing Qi; Xiaomin Luo; Yu-Bo Zhou; Xin-Hua Liao; Jia Li; Xiaojie Lu

doi:10.1021/acsmedchemlett.2c00127

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

ACS Med Chem Lett. 2022 Aug 15;13(10):1574-1581. doi: 10.1021/acsmedchemlett.2c00127. eCollection 2022 Oct 13.

Authors

Linjie Li¹, Mingbo Su^{1

2}, Weiwei Lu¹, Hongzhi Song³, Jiaxiang Liu¹, Xin Wen^{1

4}, Yanrui Suo^{1

4}, Jingjing Qi^{1

2}, Xiaomin Luo^{1

2}, Yu-Bo Zhou^{1

2

4

5}, Xin-Hua Liao⁶, Jia Li^{1

2

4

5}, Xiaojie Lu^{1

2

4}

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
³ School of Medicine, Shanghai University, Shanghai 200444, P. R. China.
⁴ University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
⁵ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400,P. R. China.
⁶ School of Life Sciences, Shanghai University, Shanghai200444, P. R. China.

Abstract

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).