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 IC 50 values between 89 and 110 nM, which were equivalent to those of erlotinib (IC 50 = 80 nm). Compound 13 was found to be an effective inhibitor of the proliferation of cancer cells (GI 50 = 0.72 µM) and demonstrated hopeful inhibitory activity of BRAF V600E (IC 50 = 58 nm), which is superior to erlotinib (IC 50 = 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.