Discovery of highly potent V600E-B-RAF kinase inhibitors: Molecular modeling study

A series of 20 triarylpyrazole derivatives containing amide or urea linker have been synthesized. Their in vitro antiproliferative activity against NCI-60 cancer cell lines panel has been reported. Upon investigating the mechanism of action at molecular level, compound 1e showed selectivity and potency against V600E-B-RAF (IC₅₀ = 390 nM). Herein, we decided to investigate the potency of the other nineteen target compounds against V600E-B-RAF. This led to discovery of several more potent compounds against that kinase. The IC₅₀ values of compounds 1g-i and 2f-i were within the range of 7-47 nM. Among them, the diarylurea compound 1i was the most potent (IC₅₀ = 7 nM). Results of docking and molecular dynamic analysis suggested the presence of consistent binding mode among our compound series with type-IIA class of inhibition pattern. Subsequently, the contribution of structural features to bioactivity were explored by means of QSAR analysis, where such effort led to the development of predictive QSAR model with significant statistical parameters (R² = 0.912, F = 38.64, Q²_LOO = 0.834, Q²_LMO = 0.816, s = 0.334). Furthermore, pharmacophoric features existed among our compound series were investigated employing molecular interaction field (MIF) analysis, which led to the development of partial least squares model consisted of four latent variables (4LV-PLS) with statistical parameters of (R²acc. = 0.98, Q²acc. = 0.81).