ARQ 069 Inhibits Enzymatic Activity by Targeting FGFR1 and FGFR2 Kinases Inactive Forms

Fibroblast growth factor receptor (FGFR) is a receptor that binds to the members of the fibroblast growth factor (FGF) family of proteins. Specifically, FGFRs, a family of receptor tyrosine kinases expressed on the cell membranes, plays an important role in the development and adult cells. Besides, FGFRs disorders are associated with a variety of cancers, such as urothelial, hepatocyte, ovarian, and lung adenocarcinoma. Due to their functional importance, FGFR is considered as a promising drug target for the treatment of various cancers. Moreover, the human fibroblast growth factor receptor (FGFR) family consists of four members: FGFR1 to FGFR4. Furthermore, the abnormal expression of FGFRs is in various solid tumors, and the abnormal expression acts as a carcinogenic signaling pathway. Enhanced selective protein kinase inhibitor is via optimizing binding interactions with less conserved inactive conformations. ARQ 069 inhibits FGFR in an enantiospecific manner.

But, how does ARQ 069 protect against cancer cells via FGFR? Let’s discuss it in detail. In the beginning, ARQ 069 is an analog of ARQ 523 and inhibits FGFR in an enantiospecific manner. In addition, ARQ 069 targets the unphosphorylated, inactive forms of FGFR1/FGFR2 kinases (IC50s of 0.84 μM and 1.23 μM, respectively). Meanwhile, ARQ 069 inhibits FGFR1/FGFR2 autophosphorylation through a mechanism that is not ATP dependent. Nonetheless, ARQ 069 reduces the degree of phosphorylation of FGFR (predominantly FGFR2) in a concentration-dependent manner, without decreasing β-actin. Finally, ARQ 069 targets the inactive forms of FGFR1 and FGFR2 kinases and inhibits their enzymatic activity. ARQ 069 exhibits at least a 20-fold preference for binding to the unphosphorylated, inactive forms of FGFR1 and FGFR2. All in all, ARQ 069 inhibits FGFR in an enantiospecific manner.



Eathiraj S, et al. J Biol Chem. 2011 Jun 10;286(23):20677-87.