Discovery of new HER2/EGFR dual kinase inhibitors based on the anilinoquinazoline scaffold as potential anti-cancer agents

Abstract

Herein, we designed and synthesized certain anilinoquinazoline derivatives bearing bulky arylpyridinyl, arylpropenoyl and arylpyrazolyl moieties at the 4′ position of the anilinoquinazoline, as potential dual HER2/EGFR kinase inhibitors. A detailed molecular modeling study was performed by docking the synthesized compounds in the active site of the epidermal growth factor receptor (EGFR). The synthesized compounds were further tested for their inhibitory activity on EGFR and HER2 tyrosine kinases. The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR with IC₅₀ equal to 2.09 and 1.94 μM, respectively, and with IC₅₀ equal to 3.98 and 1.04 μM on HER2, respectively. Furthermore, the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines, known to overexpress EGFR, showed an IC₅₀ range of 2.4 and 2.5 μM, respectively.

• Anilinoquinazoline
• EGFR
• HER2
• kinase inhibitors
• lapatinib

Acknowledgements

MA acknowledges the Swinburne University Postgraduate Research Award (SUPRA). National Computational Infrastructure (NCI) at the Australian National University for the award under the Merit Allocation Scheme, Victorian Partnership for Advanced Computing (VPAC) and Swinburne University Supercomputing Facilities are also acknowledged.