Abstract
c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.
Highlights
The proto-oncogene Met-encoded c-Met is a highly binding receptor tyrosine kinase which is the only known receptor for hepatocyte growth factor (HGF) and belongs to the RON subfamily [1]. c-Met induces a series of biological effects by binding to HGF, or by other means, to activate tyrosine kinase and regulates cell growth, migration, proliferation and survival
MM/GBSA was used to re-score the binding affinities of the c-Met type II inhibitors in induced fit docking based on London dG score to further improve the correlation between the predicted binding affinities and the binding affinities derived from the experimental data
The results revealed that compounds with potential inhibitory effects on c-Met performed well in docking and MM/GBSA [10]
Summary
The proto-oncogene Met-encoded c-Met is a highly binding receptor tyrosine kinase which is the only known receptor for hepatocyte growth factor (HGF) and belongs to the RON subfamily [1]. c-Met induces a series of biological effects by binding to HGF, or by other means, to activate tyrosine kinase and regulates cell growth, migration, proliferation and survival. Most Met TKIs competitively antagonise occupancy of the intracellular ATP binding site, preventing phosphorylation, TK activation and downstream signalling. These inhibitors are classified as type-I or type-II inhibitors depending on their mechanism of action. Type-I inhibitors adopt a U-shaped conformation, usually interact with residue MET1121 and form π–π stacking with residue TYR1230. These inhibitors bind to the ATP binding site when the kinase has a ‘DFG-in’ conformation, in which the conserved DFG motif of the activation loop being in an ‘in’ conformation [10]. Type-II inhibitors bind to the kinase when it has a ‘DFG-out’ conformation, in which the conserved DFG motif of the activation loop being in an ‘out’
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