Design, synthesis and antiproliferative, apoptotic, and immunomodulatory properties of new heteroaryl pyridine-linked 1,2,4-oxadiazoles as prospective dual EGFR/BRAFV600E inhibitors

Abstract

A novel series of heteroaryl pyridine-linked 1,2,4-oxadiazole compounds (5, 9, 14, 20a–c, 21a–c, and 22a–c) was developed, synthesized, and investigated as prospective inhibitors of EGFR and BRAF^V600E. The new compounds were investigated for antiproliferative activity against four human cancer cell lines and for safety in normal mammary epithelial cells (MCF-10A) and a normal human diploid cell line (WI-38). Compounds 20c, 21a–c, and 22b demonstrated significant antiproliferative action, with compounds 20c and 21c exhibiting the highest efficacy. Compounds 20c and 21c exhibited potent inhibition of EGFR, with IC₅₀ values of 71 and 64 nM, respectively, surpassing the reference erlotinib (IC50 = 80 nM). Moreover, compounds 20c and 21c exhibited BRAF^V600E inhibitory action with IC₅₀ values of 49 and 41 nM, respectively, which are somewhat less potent than the reference drug Vemurafenib. Assays for apoptotic markers (Caspases, Bax, Bcl-2, and p53) demonstrated that apoptosis plays a role in the reported antiproliferative effects. Compounds 20c and 21c showed a notable decrease in TNF-α and IL-6 levels compared with dexamethasone, suggesting an immunomodulatory effect. Molecular docking further validated the favorable orientation of 20c and 21c within the ATP-binding pocket of EGFR and BRAF^V600E. These findings underscore compounds 20c and 21c as innovative dual-target scaffolds with significant promise for anticancer drug development.