Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met

Tahereh Damghani,Omidreza Firuzi,Zahra Kayani,Najmeh Edraki,Fatemeh Moosavi,Somayeh Pirhadi,Mehdi Khoshneviszadeh,Luciano Saso,Motahareh Mortazavi

doi:10.1038/s41598-021-83069-4

Tahereh Damghani, Omidreza Firuzi + Show 7 more

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https://doi.org/10.1038/s41598-021-83069-4

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Abstract

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5–25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC50 values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.

Highlights

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression
The antiproliferative effects of the compounds were tested against different lung cancer and pancreatic ductal adenocarcinoma (PDAC) cell lines by sulforhodamine B (SRB) assay, and it was observed that derivatives 6d, 6e and 6f with the highest c-Met inhibitory potential suppressed the proliferation of cancer cells
The western blot analysis of 6d, 6e and 6f illustrated a significant suppression of c-Met phosphorylation. These compounds dose-dependently inhibited AsPc-1 cells grown in 3D spheroid model and induced apoptosis in the same cells

Summary

Introduction

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 μM. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They inhibited PDGFRA and FLT3 at 25 μM among a panel of 16 kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers. Class I inhibitors including FDA-approved drugs crizotinib and capmatinib, have a U-shape conformation and bind to the DFG-in conformation, while Class II inhibitors including approved drug cabozantinib, bind to the inactive DFG-out conformation that stretches from the ATP-binding s ite[16,17] (Fig. 1)

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