2. Academic Validation
  3. Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitor

Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitor

  • Eur J Med Chem. 2025 Oct 5:295:117795. doi: 10.1016/j.ejmech.2025.117795.
Dandan Zhu 1,  Zijian Zheng 2,  Huixin Huang 2,  Xiaojuan Chen 1,  Shuhong Zhang 1,  Zhuchu Chen 1,  Ting Liu 3,  Guangyu Xu 4,  Ying Fu 5,  Yongheng Chen 6
Affiliations

Affiliations

  • 1 Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 2 Key Laboratory of Chemical Biology and Traditional Chinese Medicine, Ministry of Educational of China, Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, 410081, Hunan, China.
  • 3 Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 4 Key Laboratory of Chemical Biology and Traditional Chinese Medicine, Ministry of Educational of China, Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, 410081, Hunan, China. Electronic address: gyxu@hunnu.edu.cn.
  • 5 Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. Electronic address: fuying99@csu.edu.cn.
  • 6 Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. Electronic address: yonghenc@163.com.
PMID: 40435830 DOI: 10.1016/j.ejmech.2025.117795
Abstract

Fibroblast Growth Factor receptors (FGFRs) represent promising therapeutic targets in various malignancies, yet the clinical application of FGFR covalent inhibitors has been impeded by several significant challenges, including unquantifiable target engagement, undefined off-target effects, and the emergence of drug resistance. In this study, we designed and synthesized a series of FGFR activity-based probes (ABPs) derived from FIIN-2, a pioneering selective, next-generation irreversible covalent FGFR Inhibitor with demonstrated efficacy against gatekeeper mutations. Among them, FP1 exhibited comparable inhibitory potency to FIIN-2. FP1 could facilitate precise in vitro and in situ labeling and visualization of both FGFR1-4 and their mutants. Utilizing FP1, we successfully mapped the target spectrum of FIIN-2 in MDA-MB-453 cells through activity-based protein profiling (ABPP), and established a robust framework for employing our probe as a generalizable tool to systematically evaluate the on- and off-target activities of prospective FGFR covalent inhibitors. Overall, the FGFR ABP offers a promising strategy for elucidating the engagement of FGFR, profiling the target specificity and mechanisms of covalent FGFR inhibitors, and offering potential avenues for overcoming drug resistance.

Keywords

ABP; Click chemistry; Covalent inhibitors; FGFR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-174268
    FGFR4 Inhibitor