We have identified six classes of ATP-competitive small-molecular inhibitors of protein kinase FGFR1 (fibroblast growth factor receptor 1) using computer-based rational design approach.

FGFR1 is transmembrane protein which belong to the family of receptor tyrosine kinases (RTK). FGFR's ligand is fibroblast growth factor (FGF), group of small protein. FGF binding results in receptor dimerization and kinase domain activation with consequent autophosphorylation tyrosine residues in FGFR1. Phosphorylated tyrosine residues act as docking sites for adaptor proteins leading to activation of multiple signal transduction pathways (RAS-RAF–MEK– ERK1/2, PI3K–PKB and PLC-γ/РКС). FGFR1 activation initiates cell proliferation, differentiation, migration, angiogenesis and survival.

FGFR1 play a critical role in formation of mesoderm and organogenesis of the nervous system, the mammary gland, the lungs in embryogenesis. In the adult, FGFR regulate tissue homeostasis, tissue repair, angiogenesis, inflammation, and adipocytes differentiation. Point mutations, gene amplification or overexpression of FGFR1 have been described in several oncological diseases such as lung cancer, glioma, breast cancer, prostate cancer, lymphoma, melanoma and others. Other FGFR kinases also plays role in development of cancers such as bladder cancer, myeloma, sarcoma, gastric cancer and cervical cancer.

FGFR1 inhibitors can be implemented for treatment of cancers with FGFR1 altered activity. FGFR1 inhibitors have revealed high efficiency in experiments in vitro and in in vivo in various types of tumors with increased activity of this kinase. Currently have been founded several classes of inhibitors of FGFR1, many of them are under clinical trials.

Our search of inhibitors of FGFR1 started from receptor-based virtual screening of our department chemical compounds collection. To increase the percentage found inhibitors we used verification protocol of screening and fine-tuning the parameters on set FGFR1 inhibitors with known position in the binding site. As a result, we have 32 classes of inhibitors with IC₅₀ less than 20 µM, representing 6% of the total number of tested compounds. For the most promising classes of inhibitors was made searching and testing analogues from the collection of chemical compounds. The most active classes of compounds were optimized by direct chemical synthesis and tested on antiproliferative activity in collaboration with the department of human genetics. Below are inhibitors of the published data: