BIOMAT Database Logo BIOMAT Database Logo

Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4. 2024

Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery.

UI MeSH Term Description Entries
D008113 Liver Neoplasms Tumors or cancer of the LIVER. Cancer of Liver,Hepatic Cancer,Liver Cancer,Cancer of the Liver,Cancer, Hepatocellular,Hepatic Neoplasms,Hepatocellular Cancer,Neoplasms, Hepatic,Neoplasms, Liver,Cancer, Hepatic,Cancer, Liver,Cancers, Hepatic,Cancers, Hepatocellular,Cancers, Liver,Hepatic Cancers,Hepatic Neoplasm,Hepatocellular Cancers,Liver Cancers,Liver Neoplasm,Neoplasm, Hepatic,Neoplasm, Liver
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D006528 Carcinoma, Hepatocellular A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested. Hepatocellular Carcinoma,Hepatoma,Liver Cancer, Adult,Liver Cell Carcinoma,Liver Cell Carcinoma, Adult,Adult Liver Cancer,Adult Liver Cancers,Cancer, Adult Liver,Cancers, Adult Liver,Carcinoma, Liver Cell,Carcinomas, Hepatocellular,Carcinomas, Liver Cell,Cell Carcinoma, Liver,Cell Carcinomas, Liver,Hepatocellular Carcinomas,Hepatomas,Liver Cancers, Adult,Liver Cell Carcinomas
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D051499 Receptor, Fibroblast Growth Factor, Type 4 A fibroblast growth factor receptor that is mainly expressed in LUNG; KIDNEY; PANCREAS; and SPLEEN. It also plays an important role in SKELETAL MUSCLE development and can contribute to NEOPLASTIC CELL TRANSFORMATION. Fibroblast Growth Factor Receptor 4,Fibroblast Growth Factor Receptors 4,Receptor 4, Fibroblast Growth Factor
D061986 MCF-7 Cells An estrogen responsive cell line derived from a patient with metastatic human breast ADENOCARCINOMA (at the Michigan Cancer Foundation.) MCF7 Cells,Michigan Cancer Foundation 7 Cells,Cell, MCF-7,Cell, MCF7,Cells, MCF-7,Cells, MCF7,MCF 7 Cells,MCF-7 Cell,MCF7 Cell

Related Publications

Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors.
December 2021, European journal of medicinal chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.
March 2022, Journal of medicinal chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants.
October 2023, European journal of medicinal chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, synthesis, and biological evaluation of quinazoline derivatives with covalent reversible warheads as potential FGFR4 inhibitors.
April 2022, Bioorganic chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, synthesis, and anticancer evaluation of arylurea derivatives as potent and selective type II irreversible covalent FGFR4 inhibitors.
May 2023, Bioorganic & medicinal chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors.
November 2022, Journal of medicinal chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, synthesis and biological activity evaluation of novel covalent S-acylation inhibitors.
April 2023, Molecular diversity,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Novel 7-formyl-naphthyridyl-ureas derivatives as potential selective FGFR4 inhibitors: Design, synthesis, and biological activity studies.
May 2019, Bioorganic & medicinal chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, synthesis, and biological evaluation of indazole derivatives as selective and potent FGFR4 inhibitors for the treatment of FGF19-driven hepatocellular cancer.
March 2021, European journal of medicinal chemistry,
Xiaojuan Chen, and Huiliang Li, and Qianmeng Lin, and Shuyan Dai, and Lingzhi Qu, and Ming Guo, and Lin Zhang, and Jiaxuan Liao, and Hudie Wei, and Guangyu Xu, and Longying Jiang, and Yongheng Chen
Design, synthesis, and biological evaluation of novel covalent inhibitors targeting focal adhesion kinase.
December 2021, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!