Discovery of anticancer agents with c-Met inhibitory potential by virtual and experimental screening of a chemical library

Motahareh Mortazavi, Elaheh Raufi, Tahereh Damghani, Mehdi Khoshneviszadeh, Najmeh Edraki, Masoomeh Eskandari, Elisa Giovannetti, Godefridus J. Peters, Somayeh Pirhadi, Omidreza Firuzi

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2 Citations (Scopus)

Abstract

c-Met receptor tyrosine kinase has recently emerged as an important target with therapeutic implications in pancreatic cancer. In this study, we carried out a docking virtual screening on an in-house library of 441 synthesized compounds and selected the compounds with the best interactions with the c-Met protein to be subjected to experimental tests. Ten compounds belonging to 3 different classes of chemical structures were selected for this purpose and their antiproliferative effects were studied against 4 pancreatic ductal adenocarcinoma (PDAC) cell lines including AsPC-1, Suit-2, Panc-1 and Mia-Paca-2 cells, primary PDAC cells and also c-Met amplified EBC-1 cell line by sulforhodamine-B assay. Apoptosis induction was examined by Hoechst 33258 staining and annexin V-FITC/propidium iodide flow cytometric assay. The best compound was also assayed in three-dimensional cultures of AsPC-1 cells and its c-Met inhibitory potential was studied by immunoblotting and a homogenous time resolved fluorescence (HTRF) assay. The compound with a phenanthrotriazine hydrazinyl scaffold bearing nitrophenyl pendant (PhTH) was the most active derivative, with IC50 values in the range of 5–8 μM. This compound exerted antiproliferative effect against AsPC-1 cells also in the presence of hepatocyte growth factor (HGF). PhTH induced apoptosis, dose-dependently inhibited spheroid growth, inhibited c-Met activity in cell-free HTRF assay and also inhibited the phosphorylation of c-Met and its downstream effector ERK1/2 in AsPC-1 cells. Molecular docking and dynamics simulation and MM-PBSA analysis confirmed close interactions of PhTH with c-Met kinase domain. Some of the tested compounds in this study seem to be potential c-Met inhibitors with promising activities against PDAC cells.
Original languageEnglish
Article number175395
JournalEuropean journal of pharmacology
Volume938
DOIs
Publication statusPublished - 5 Jan 2023

Keywords

  • Anticancer agents
  • Computational screening
  • Gastrointestinal tumors
  • Kinase inhibitors
  • Targeted therapies

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