Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors

Abstract

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has been attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines(SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good antiproliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM and potently inhibited the SNU-16 and MCF-7 cancer cell with IC50 values of 0.71, 1.26 µM, respectively. And 8e inhibited the grow of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions are quite similar in our molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings 5-amino-1H-pyrazole-1-carbonyl might be served as a promising template of FGFR inhibitor.

Virtual Screening, Molecular Dynamics, MM-PBSA and In-silico Studies in Search of Potent Novel Fibroblast Growth Factor Receptors 4 Inhibitor

“…Previously reported active compounds having affinity to FGFR4 with IC 50 ≤100nM were collected in one database entitled with FGFR4 inhibitors [3,9,18,19] . These compounds were prepared using Molecular Operating Environment (MOE) version 2019.01 software through three steps which are washing, partial charge calculation and energy minimization using force field MMFF94x with the default gradient 0.1 RMS kcal/(mol.Å).…”

“…The binding pocket residues of FGFR4 protein were defined based on the previously reported binding mode of FGF401 (a potent FGFR4 inhibitor) [3,9,18] . In order to assess the reliability and robustness of our docking algorithm, the minimized form of FGF401 was first docked into the binding pocket of FGFR4 protein using different replacement, refinement methods, scoring functions in order to reach the optimum docking algorithm.…”

“…Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases (RTKs) that play a crucial role in various cellular processes such as cell proliferation, differentiation, migration, and survival. Studies have shown that, the differential expression of the ligand fibroblast growth factors (FGFs) and their receptors throughout the developing and mature gastrointestinal tract that seem to play an important role in modulating gut development and epithelial repair mechanisms after injury [1][2][3] .…”