Imidazothiazole-based Potent Inhibitors of V600E-B-RAF Kinase with Promising Anti-Melanoma Activity: Biological and Computational Studies.
Journal of enzyme inhibition and medicinal chemistry(2020)
Abstract
A series of imidazothiazole derivatives possessing potential activity against melanoma cells were investigated for molecular mechanism of action. The target compounds were tested against V600E-B-RAF and RAF1 kinases. Compound 1zb is the most potent against both kinases with IC50 values 0.978 and 8.2 nM, respectively. It showed relative selectivity against V600E mutant B-RAF kinase. Compound 1zb was also tested against four melanoma cell lines and exerted superior potency (IC50 0.18-0.59 µM) compared to the reference standard drug, sorafenib (IC50 1.95-5.45 µM). Compound 1zb demonstrated also prominent selectivity towards melanoma cells than normal skin cells. It was further tested in whole-cell kinase assay and showed in-cell V600E-B-RAF kinase inhibition with IC50 of 0.19 µM. Compound 1zb induces apoptosis not necrosis in the most sensitive melanoma cell line, UACC-62. Furthermore, molecular dynamic and 3D-QSAR studies were done to investigate the binding mode and understand the pharmacophoric features of this series of compounds.
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Key words
Apoptosis,imidazothiazole,melanoma,modelling,V600E-B-RAF
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