الفهرس 
Overview of cancer incidence and mortality
Common EGFR mutationsOnly 14 pages are availabe for public view
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Abstract
One of the most important targets to manage cancer cell growth is through inhibition of epidermal growth factor receptor (EGFR). EGFR is a transmembrane receptor tyrosine kinase that is present on the cell surface and display an important role in the process of intracellular signaling, hence mediating morphogenesis and differentiation. EGFR overexpression and/or mutation cause angiogenesis, invasion of neighboring tissues, and proliferation, leading to the development of many types of cancer, especially solid tumors such as non-small cell (NSC) lung cancer, prostate cancer, and colon cancer. There are four generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs), each generation is developed to overcome a mutation to the previous one. 1,4-Dihydropyridine (DHP) scaffold is one of the most interesting cores in the field of pharmaceutical chemistry due to its versatile and promising biological activities, especially anticancer activity. Hexahydroquinoline (HHQ) is a DHP derivative in which a cyclohexane ring is fused to the DHP ring. In this study, thirty-two HHQ derivatives were designed and synthesized aiming to develop new anticancer agents. Chemical structures of the synthesized target compounds where confirmed via using IR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis. Moreover, X-ray crystallography and optical rotation were achieved to confirm enantiomerism. All the synthesized compounds were biologically evaluated for their anticancer activity against 60 cancer cell lines of the NCI. Thirteen compounds displayed moderate to strong activity against NCI 60 cancer cell lines, with GI % mean up to 74% for compound 10c. Expending erlotinib as a reference drug, 13 compounds; 6a, 6c-f, 6i, 8b-c, 8e, and 10ad, were verified for their inhibitory activities to EGFRWT, EGFRT790M, and EGFRL858R where compound 10d reported the greatest activity with IC50 = 0.097 μM, 0.280 μM, and 0.051 μM, respectively compared to erlotinib (IC50 = 0.082 μM, 0.342 μM, and 0.055 μM, respectively). Compounds 10c and 10d were assessed for their safety profile by testing their selective cytotoxicity towards cancer cells compared to normal lung cells (IMR-90), using erlotinib as a reference drug. Compounds 10c and 10d disrupted the cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92 (Hopkins-92), cell line. Furthermore, compounds 10c and 10d established their cytotoxic activity via the apoptotic mechanism rather than the necrotic pathway. In silico studies using Molsoft software and the SwissADME web tool were achieved to assess the pharmacokinetic and drug-likeness of target compounds. A molecular docking study for the R- and S-enantiomers of selected analogues was performed to understand their potential binding interactions and affinities in the active sites of three versions of EGFRs, where S-enantiomer demonstrated higher binding affinity than the Renantiomer.