Imidazothiazole-based potent inhibitors of V600E-B-RAF kinase with promising anti-melanoma activity: biological and computational studies

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.

Keywords: Apoptosis; V600E-B-RAF; imidazothiazole; melanoma; modelling.