New thieno[2,3-d]pyrimidine derivatives as EGFR^WT and EGFR^T790M inhibitors: Design, synthesis, antiproliferative activities, docking studies, ADMET, toxicity, MD simulation studies

A series of thieno[2,3-d]pyrimidines were designed and synthesized as epidermal growth factor receptor (EGFR) inhibitors. These compounds were tested for their ability to inhibit MCF-7 and A549 cancer cells. The most active compound, 12c, inhibited the growth of both cell lines, with IC50 values of 15.67 and 12.16 mu M, respectively. It was found that 12c had inhibitory effects on both EGFR(WT) and EGFR(T790M) isoforms, with inhibitory partialities of 37.50 and 148.90 nM, respectively. Additionally, 12c was found to be safer than erlotinib against normal cell lines (IC50 = 38.61 mu M). Compound 12c induced early and late apoptosis in A549 cells and arrested cell growth at G1 and G2/M phases. 12c was also found to increase caspases 3 and 8 ratios. Molecular docking indicated the correct binding modes of the synthesized compounds. MD simulations, MM-GBSA, and PLIP studies confirmed the precise binding of 12c to the EGFR protein over 100 ns.