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

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 (GI(50) = 0.72 mu M) 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.

Automated summary

Dual EGFR and BRAF(V600E) inhibitors have been developed, showing strong antiproliferative activity and dual inhibition activity on EGFR and BRAF(V600E) in vitro.