Imidazothiazole-based potent inhibitors of V600EB-RAF kinase with promising anti-melanoma activity: biological and computational studies
- Imidazothiazole-based potent inhibitors of V600EB-RAF kinase with promising anti-melanoma activity: biological and computational studies
- 오창현; 이봉상; 전홍렬; Hanan S. Anbar; Mohammed I. El-Gamal; Hamadeh Tarazi; 권도우
- Apoptosis; imidazothiazole; melanoma; modelling; V600E-B-RAF
- Issue Date
- Journal of enzyme inhibition and medicinal chemistry
- VOL 35, NO 1-1726
- 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 mM) compared to the reference standard drug, sorafenib (IC50 1.95-5.45 mM). 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 mM. Compound 1zb induces apoptosis not necrosis in the most sensitive melanoma cell line, UACC-62. Furthermore, molecular dynamic and 3DQSAR studies were done to investigate the binding mode and understand the pharmacophoric features ofthis series of compounds.
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