Lead compound bearing caffeic scaffold induces EGFR suppression in solid tumor cancer cells

Abstract

Available online xxxKeywords: Caffeic acid derivatives EGFR inhibitor Triple-negative breast cancer Non-small cell lung cancer Molecular modeling Abbreviations: CA, caffeic acid CAPE, caffeic acid phenethyl ester EGFR, epidermal growth factor receptor RTK, receptor tyrosine kinase TNBC, triple-negative breast cancer a b s t r a c t A small molecule EGFR inhibitor, 4-(2-(3-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)ureido) vinyl)-1,2-phenylene diacetate (CIU1) was designed in silico by using caffeic scaffold as core structure. The designed compound showed anti-proliferative action against different solid tumor cell lines, particularly metastatic breast cancer cells. CIU1 inhibited the growth of EGFR-overexpressing MDA-MB-468 triple-negative breast cancer cells and wild-type nonsmall-cell lung cancer H460 cells with IC 50 values of 8.96 mM and 12.98 mM, respectively, these anti-proliferative effects of CIU1 were comparable to gefitinib (a specific EGFR inhibitor) or lapatinib (a dual EGFR and HER2 tyrosine kinase inhibitor). Interestingly CIU1 effectively inhibited the invasive hormone-dependent MCF-7 cancer cells with an IC 50 2.34 mM. The immunoblot analyses revealed that CIU1 induced programmed cell death and suppressed EGFR expression in EGFR-overexpressing breast cancer (MDA-MB468) and lung cancer (PC-9) cells. The findings substantiated our design strategy and demonstrated the potential of CIU1 as new lead for further optimization in the development of anticancer drugs against advanced solid tumors.

Natural Products as Chemopreventive Agents by Potential Inhibition of the Kinase Domain in ErbB Receptors

“…Given the prominent importance of EGFR signaling in cancer development, scientists have developed the following strategies: anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors (TKIs) [ 18 ]. Anti-EGFR antibodies, e.g., cetuximab and panitumumab, bind to the extracellular domain of EGFR monomer and compete against endogenous ligands by receptor binding, blocking ligand-induced receptor activation.…”

“…Anti-EGFR antibodies, e.g., cetuximab and panitumumab, bind to the extracellular domain of EGFR monomer and compete against endogenous ligands by receptor binding, blocking ligand-induced receptor activation. Small molecule EGFR inhibitors, such as erlotinib, gefitinib and lapatinib, compete specifically with ATP for bind to the catalytic tyrosine kinase domain, inhibiting autophosphorylation processes and downstream signaling of cancer cells [ 18 ]. The inhibition of EGFR and its related proteins is considered as a standard approach in cancer investigations.…”