Fu Junjie, Xia Amy, Qi Xin
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610.
Columbia University, New York, NY 10027.
Medchemcomm. 2016;7:1183-1189. doi: 10.1039/C6MD00121A. Epub 2016 Apr 14.
Drug development targeting fibroblast growth factor receptors (FGFRs) represents an emerging theme in the field of medicinal chemistry. Considering the fact that most of the currently identified FGFR agonists are long chain peptides with limited stability, the discovery of novel non-peptide FGFR ligands is still highly demanded. A linear one-bead-one-compound peptoid (oligomers of N-substituted glycine units) library with a theoretical diversity of 10 was designed and synthesized. Microarray-based screening led to the identification of four hit sequences - as FGFR1α ligands, which were further confirmed using both solution-phase and solid-phase binding assays. Western blot results indicated that peptoids - activated FGFR signaling pathways, resulting in increased levels of p-Akt and p-ERK in different cell lines. Our work discovered novel peptoid ligands as FGFR agonists, shedding new light on FGFR-based drug discovery.
靶向成纤维细胞生长因子受体（FGFRs）的药物研发是药物化学领域一个新兴的研究方向。鉴于目前已鉴定出的大多数FGFR激动剂都是稳定性有限的长链肽，因此新型非肽类FGFR配体的发现仍备受期待。设计并合成了一个理论多样性为10的线性单珠单化合物类肽（N-取代甘氨酸单元的寡聚物）文库。基于微阵列的筛选鉴定出了四个命中序列——作为FGFR1α配体，随后使用溶液相和固相结合试验进一步确认。蛋白质印迹结果表明，类肽激活了FGFR信号通路，导致不同细胞系中p-Akt和p-ERK水平升高。我们的研究发现了新型类肽配体作为FGFR激动剂，为基于FGFR的药物研发提供了新的思路。
