Quinazoline derivatives with dual EGFR and VEGFR-2 inhibition: insights from docking, molecular dynamics, and in vivo studies

Abstract

Tumor growth, angiogenesis, and metastasis are influenced by EGFR and VEGFR-2; therefore, dual targeting of EGFR and VEGFR-2 is an attractive approach for cancer management. Here, novel quinazoline analogues 4-23 were designed and synthesized as dual EGFR and VEGFR-2 TK inhibitors. In vitro enzymatic inhibitory activities against EGFR and VEGFR-2 and cytotoxic activities against lung A549 and breast MCF-7 cancer cell lines were evaluated. Compound 18 had potent cytotoxicity against A549 cells with an IC50 value of 9.41 µM, compared with 9.43 µM for sorafenib. On the other hand, compound 15 had potent cytotoxicity against MCF-7 cells with an IC50 value of 5.08 µM, compared with 4.94 µM for sorafenib, and poor cytotoxicity against A549 cells. Compound 15 exhibited a remarkable dual EGFR and VEGFR-2 inhibitory activity with IC50 values of 0.04 and 0.086 µM, compared with sorafenib 0.035 and 0.09 µM, respectively, while compound 18 exhibited promising inhibitory activity against EGFR with an IC50 value of 0.07 µM and moderate activity against VEGFR-2. For apoptosis investigation, compound 15 significantly stimulated total apoptotic breast cancer cell death by 27.17-fold, arresting the cell proliferation at the G2/M-phase, while compound 18 significantly stimulated apoptotic lung cancer cell death by 7.95-fold. In vivo studies showed that compound 15 exhibited tumor inhibition by 72%, compared with 65% inhibition for the sorafenib-treated group. Finally, docking studies and molecular dynamic simulations were performed to explore the probable binding modes. Taken together, in vitro, in silico, and in vivo results revealed that compound 15 had high drug potential as a dual-target inhibitor of EGFR/VEGFR-2 to inhibit breast cancer growth and apoptosis.

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