School of Pharmaceutical Sciences, Wenzhou Medical College, Wenzhou 325035, China.
Trends Pharmacol Sci. 2012 Oct;33(10):531-41. doi: 10.1016/j.tips.2012.07.001. Epub 2012 Aug 9.
The fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases: FGFR1-4. Upon ligand binding, FGFRs activate an array of downstream signaling pathways, such as the mitogen activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K)/Akt pathways. These FGFR cascades play crucial roles in tumor cell proliferation, angiogenesis, migration, and survival. The combination of knockdown studies and pharmaceutical inhibition in preclinical models demonstrates that FGFRs are attractive targets for therapeutic intervention in cancer. Multiple FGFR inhibitors with various structural skeletons have been designed, synthesized, and evaluated. Reviews on FGFRs have recently focused on FGFR signaling, pathophysiology, and functions in cancer or other diseases. In this article, we review recent advances in structure-activity relationships (SAR) of FGFR inhibitors, as well as the FGFR-targeting drug design strategies currently employed in targeting deregulated FGFRs by antibodies and small molecule inhibitors.
成纤维细胞生长因子受体（FGFR）家族包括四个高度保守的受体酪氨酸激酶：FGFR1-4。配体结合后，FGFRs 激活一系列下游信号通路，如丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇 3-激酶（PI3K）/Akt 通路。这些 FGFR 级联反应在肿瘤细胞增殖、血管生成、迁移和存活中发挥着关键作用。在临床前模型中进行的敲低研究和药物抑制的组合表明，FGFR 是癌症治疗干预的有吸引力的靶点。已经设计、合成和评估了具有各种结构骨架的多种 FGFR 抑制剂。最近的 FGFR 综述集中在 FGFR 信号转导、病理生理学以及在癌症或其他疾病中的功能上。在本文中，我们回顾了 FGFR 抑制剂的结构-活性关系（SAR）的最新进展，以及目前通过抗体和小分子抑制剂靶向失调的 FGFR 所采用的 FGFR 靶向药物设计策略。
