Discovery of new cyanopyridine/chalcone hybrids as dual inhibitors of EGFR/BRAFV600E with promising antiproliferative properties

Abstract

As dual EGFR and BRAF^V600E inhibitors, 2-(3-cyano-4,6-bis(aryl)-2-oxo-1,2-dihydropyridine-1-yl)-N-(4-cinnamoylphenyl) acetamide derivatives 8-20 were developed. Compounds 8, 12, and 13 showed strong antiproliferative activity when the target compounds were synthesized and tested in vitro against four cancer cell lines. These hybrids have a dual inhibition activity on EGFR and BRAF^V600E , according to in vitro studies. The EGFR was inhibited by compounds 8, 12, and 13 with IC₅₀ values between 89 and 110 nM, which were equivalent to those of erlotinib (IC₅₀ = 80 nm). Compound 13 was found to be an effective inhibitor of the proliferation of cancer cells (GI₅₀ = 0.72 µM) and demonstrated hopeful inhibitory activity of BRAF^V600E (IC₅₀ = 58 nm), which is superior to erlotinib (IC₅₀ = 65 nm). Compound 13 caused apoptosis and showed cell cycle arrest in the G0/G1phase in a study on the MCF-7 cell line. The new compounds can fit tightly into the active sites of EGFR and BRAF^V600E kinases, according to molecular docking analyses.

Keywords: antiproliferative; apoptosis; docking; hybridization; kinases.