2. Academic Validation
  3. Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads

Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads

  • J Am Chem Soc. 2025 May 7;147(18):15469-15481. doi: 10.1021/jacs.5c01712.
Xinyuan Wu 1 2,  Jiayi Pan 1 2,  Rufeng Fan 1 2,  Yiwei Zhang 1 2,  Chao Wang 1 2,  Guoliang Wang 1 3,  Jiaxiang Liu 1,  Mengqing Cui 1,  Jinfeng Yue 1,  Rui Jin 1,  Zhiqiang Duan 1,  Mingyue Zheng 1 2,  Lianghe Mei 4,  Lu Zhou 5,  Minjia Tan 1 2 6,  Jing Ai 1 2 7,  Xiaojie Lu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China.
  • 4 Suzhou Institute of Materia Medica, Suzhou, Jiangsu 215123, China.
  • 5 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 6 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 7 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 40292872 DOI: 10.1021/jacs.5c01712
Abstract

Covalent small molecule drugs have emerged as a crucial support in precision therapy due to their high selectivity and robust potency. Covalent DNA-encoded chemical library (CoDEL) technology is an advanced platform for covalent drug discovery. However, the application of CoDELs is constrained by a single-residue focus and limited warhead diversity. Here we report a method to identify residue-selective inhibitors using CoDELs with diverse warheads targeting multiple distinct residues. We systematically evaluated the reactivity of 17 warheads with 9 nucleophilic Amino acids of FGFR2 and then constructed CoDELs comprising 24.8 million compounds. These CoDELs enabled the identification of active covalent inhibitors targeting cysteine, lysine, arginine, or glutamic acid. The lysine-targeting inhibitor engaged a novel reactive site. The arginine-targeting inhibitor demonstrated subtype selectivity and overcame drug resistance. The glutamic acid-targeting inhibitor validated the druggability of this unconventional covalent residue site. These findings suggest that our work could potentially expand the target space of covalent drugs and promote precision therapy by harnessing the power of the CoDELs.

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