基于结构的FGFR4双弹头共价抑制剂设计
Structure-based design of a dual-warhead covalent inhibitor of FGFR4.
作者信息
Chen Xiaojuan, Li Huiliang, Lin Qianmeng, Dai Shuyan, Yue Sitong, Qu Lingzhi, Li Maoyu, Guo Ming, Wei Hudie, Li Jun, Jiang Longying, Xu Guangyu, Chen Yongheng
机构信息
Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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, Hunan, China.
出版信息
Commun Chem. 2022 Mar 17;5(1):36. doi: 10.1038/s42004-022-00657-9.
The 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.
成纤维细胞生长因子19（FGF19）/成纤维细胞生长因子受体4（FGFR4）信号通路在多种癌症中发挥关键作用，如肝细胞癌（HCC）。FGFR4被认为是治疗HCC的一个有前景的靶点。目前，所有FGFR共价抑制剂都靶向两个半胱氨酸（Cys477和Cys552）之一。在此，我们设计并合成了一种双弹头共价FGFR4抑制剂CXF - 009，靶向FGFR4的Cys477和Cys552。我们报道了FGFR4与CXF - 009的共晶体结构，其呈现出双弹头共价结合模式。CXF - 009对FGFR4的选择性比对FGFR1 - 3和其他激酶更强。CXF - 009还能有效抑制FGFR4的单半胱氨酸突变体FGFR4（C477A）和FGFR4（C552A）。总之，我们的研究提供了一种双弹头共价FGFR4抑制剂，它可以共价靶向FGFR4的两个半胱氨酸。据我们所知，CXF - 009是首个被报道的与FGFR4中的两个半胱氨酸残基形成双弹头共价键的抑制剂。CXF - 009还有潜力克服药物诱导的FGFR4耐药突变，可能作为未来抗癌药物发现的先导化合物。
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