Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads
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.
Authors
- Guoliang Wang (ORCID: https://orcid.org/0009-0008-0070-5920)
- Xiaojie Lu (ORCID: https://orcid.org/0000-0002-3600-288X)
- Lu Zhou (ORCID: https://orcid.org/0000-0002-6807-2647)
- Rui Jin (ORCID: https://orcid.org/0000-0003-4544-6535)
- Lianghe Mei
- Jinfeng Yue
- Xinyuan Wu (ORCID: https://orcid.org/0009-0000-7565-6811)
- Chao Wang (ORCID: https://orcid.org/0000-0003-3137-1632)
- Jian Pan (ORCID: https://orcid.org/0000-0002-0292-5141)
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Zhiqiang Duan (ORCID: https://orcid.org/0009-0003-4097-4336)
- Minjia Tan (ORCID: https://orcid.org/0000-0002-6784-9653)
- Rufeng Fan
- Jing Ai (ORCID: https://orcid.org/0000-0003-3717-981X)
- Jiaxiang Liu
- Mengqing Cui
- Yiwei Zhang (ORCID: https://orcid.org/0000-0003-1257-8435)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Xinjiang Institute of Materia Medica (CN)
- Shanghai Institute of Materia Medica (CN)
- Advanced Research Institute (US)
- Drug Discovery Laboratory (Norway) (NO)
- University of Chinese Academy of Sciences (CN)
- State Key Laboratory of Drug Research
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-04-28
- DOI
- https://doi.org/10.1021/jacs.5c01712
- Citations
- 20
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 16.12
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences