Structure-based design of a dual-warhead covalent inhibitor of FGFR4

• DOI: 10.1038/s42004-022-00657-9
• Publication Date: 2022-03-17T11:04:45Z
• Authors: Xiaojuan Chen; Huiliang Li; Qianmeng Lin; Shuyan Dai; Sitong Yue; Lingzhi Qu; Maoyu Li; Ming Guo; Hudie Wei; Jun Li; Longying Jiang; Guangyu Xu; Yongheng Chen
• Keywords: Chemistry; 0303 health sciences; 03 medical and health sciences; QD1-999; Article; 3. Good health

AbstractThe fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor, CXF-009, targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with CXF-009, which exhibits a dual-warhead covalent binding mode. CXF-009 exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4. CXF-009, to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4. CXF-009 also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery.