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

## TL;DR

Scientists designed new compounds that effectively inhibit two cancer-related proteins, EGFR and BRAFV600E, with potential for anticancer drug development.

## Contribution

The paper introduces new dual EGFR/BRAFV600E inhibitors with improved antiproliferative and immunomodulatory effects.

## Key findings

- Compounds 20c and 21c showed potent inhibition of EGFR and BRAFV600E with IC50 values below reference drugs.
- Compounds 20c and 21c induced apoptosis and reduced pro-inflammatory cytokines like TNF-α and IL-6.
- Molecular docking confirmed the favorable binding orientation of 20c and 21c in the ATP-binding pockets of EGFR and BRAFV600E.

## 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 BRAFV600E. 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 BRAFV600E 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 BRAFV600E. These findings underscore compounds 20c and 21c as innovative dual-target scaffolds with significant promise for anticancer drug development.

Vemurafenib triggers resistance via EGFR feedback upregulation, compound 21c achieves a “vertical blockade” by simultaneously inhibiting EGFR and mutant BRAF.