摘要
背景:成纤维细胞生长因子(FGF)家族由23种高度调节的单体蛋白组成,这些蛋白调节过多的发育和病理生理过程,包括组织修复,伤口愈合,血管生成和胚胎发育。糖胺聚糖,肝素可促进FGF与成纤维细胞生长因子受体(FGFR)(一种酪氨酸激酶受体)的结合。活化的FGFR磷酸化酪氨酸激酶残基,介导下游信号通路(如RAS-MAPK,PI3K-AKT,PLCγ和STAT)的诱导。由于基因扩增,FGF激活突变,染色体重排,整合和致癌融合,FGF / FGFR信号失调经常发生在癌症中。异常的FGFR信号传导也影响器官发生,胚胎发育,组织稳态,并与细胞增殖,血管生成,癌症和其他病理生理学改变有关。 目的:这篇全面的综述将讨论FGF的生物学,化学和功能,及其在伤口愈合,糖尿病,组织修复和再生以及脂肪肝疾病中的当前应用。此外,还详细讨论了FGFR信号传导中的特定像差以及靶向FGFR并有助于缓解各种疾病(例如癌症)的药物。 结论:FGFR信号抑制剂是治疗几种类型癌症的有前途的药物。 FGF / FGFR靶向疗法的临床益处由于其他RTK信号传导机制的激活或由于取消了对FGFR的药物抑制活性的突变而受到阻碍。因此,针对FGF / FGFR靶向疗法具有不同作用机制的药物的开发是一些临床前和临床研究的近期焦点。
关键词: 成纤维细胞生长因子,成纤维细胞生长因子受体,FGF / FGFR信号传导,异常FGFR信号传导,癌症。
图形摘要
Current Drug Targets
Title:Targeting Drugs Against Fibroblast Growth Factor(s)-Induced Cell Signaling
Volume: 22 Issue: 2
关键词: 成纤维细胞生长因子,成纤维细胞生长因子受体,FGF / FGFR信号传导,异常FGFR信号传导,癌症。
摘要:
Background: The fibroblast growth factor (FGF) family is comprised of 23 highly regulated monomeric proteins that regulate a plethora of developmental and pathophysiological processes, including tissue repair, wound healing, angiogenesis, and embryonic development. Binding of FGF to fibroblast growth factor receptor (FGFR), a tyrosine kinase receptor, is facilitated by a glycosaminoglycan, heparin. Activated FGFRs phosphorylate the tyrosine kinase residues that mediate induction of downstream signaling pathways, such as RAS-MAPK, PI3K-AKT, PLCγ, and STAT. Dysregulation of the FGF/FGFR signaling occurs frequently in cancer due to gene amplification, FGF activating mutations, chromosomal rearrangements, integration, and oncogenic fusions. Aberrant FGFR signaling also affects organogenesis, embryonic development, tissue homeostasis, and has been associated with cell proliferation, angiogenesis, cancer, and other pathophysiological changes.
Objective: This comprehensive review will discuss the biology, chemistry, and functions of FGFs, and its current applications toward wound healing, diabetes, repair and regeneration of tissues, and fatty liver diseases. In addition, specific aberrations in FGFR signaling and drugs that target FGFR and aid in mitigating various disorders, such as cancer, are also discussed in detail.
Conclusion: Inhibitors of FGFR signaling are promising drugs in the treatment of several types of cancers. The clinical benefits of FGF/FGFR targeting therapies are impeded due to the activation of other RTK signaling mechanisms or due to the mutations that abolish the drug inhibitory activity on FGFR. Thus, the development of drugs with a different mechanism of action for FGF/FGFR targeting therapies is the recent focus of several preclinical and clinical studies.
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Cite this article as:
Targeting Drugs Against Fibroblast Growth Factor(s)-Induced Cell Signaling, Current Drug Targets 2021; 22 (2) . https://dx.doi.org/10.2174/1389450121999201012201926
DOI https://dx.doi.org/10.2174/1389450121999201012201926 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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