小分子抗肿瘤FGFR抑制剂与FGFR蛋白的作用关系研究及研发进展

Development and ligand-protein interaction of small molecule anti-tumor FGFR inhibitors

成纤维细胞生长因子受体(fibroblast growth factor receptors,FGFRs)为受体酪氨酸激酶(receptor tyrosine kinases,RTKs)超家族的一员。成纤维细胞生长因子(fibroblast growth factors,FGFs)能与FGFRs高亲和力结合,参与许多生物学过程,如调节器官发育,新生血管生成,细胞增殖、迁移、抗凋亡等。FGFR基因的激活突变和扩增,导致FGFR蛋白的扩增,与许多恶性肿瘤的发生、发展有着密不可分的联系。近年来,报道了多种化学骨架的小分子FGFR抑制剂,其中大部分已应用到临床抗癌研究中。本文综述了目前处于临床研究阶段的第二代选择性FGFR小分子抑制剂,并关注其与FGFR蛋白的作用关系,以期为FGFR小分子抑制剂的设计提供一些参考。

Fibroblast growth factor receptors （FGFRs） are in the superfamily of receptor tyrosine kinases＇ （RTKs）. Fibroblast growth factors （FGFs） bind to FGFRs with high-affinity, involving in many biological processes, such as the regulation of organ development, angiogenesis, cell proliferation, migration and anti-apoptosis. The activating mutations and amplification of the FGFR gene, resulting in FGFR protein amplification, are closely associated with the development and progression of many malignancies in human. In recent years, various small molecule FGFR inhibitors with different chemical backbones are designed, synthesized, and mainly applied to the clinical anti-cancer research. This article is devoted to review of selective second generation of small molecule FGFR inhibitors that are currently used in clinical trials, and the interaction with the FGFR protein, in order to provide strategies to the design of small molecule FGFR inhibitors.