Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors

Abstract

Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition. From the experimental screening, all chalcones seemed to be more active against the A431 than the A549 cell line, with chalcones 1c, 2a, 3e, 4e, and 4t showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC50 values of < 10 µM against A431 cells. Moreover, these five chalcones showed more potent on H1975 (T790M/L858R mutation) than H1650 (exon 19 deletion E746-A750) cell lines. Only three chalcones (1c, 2a and 3e) had an inhibitory activity against EGFR-TK with a relative inhibition percentage that was close to the approved drug, erlotinib. Molecular dynamics studies on their complexes with EGFR-TK domain in aqueous solution affirmed that they were well-occupied within the ATP binding site and strongly interacted with seven hydrophobic residues, including the important hinge region residue M793. From the above information, as well as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, all three chalcones could serve as lead compounds for the development of EGFR-TK inhibitors.

Identification of Vinyl Sulfone Derivatives as EGFR Tyrosine Kinase Inhibitor: In Vitro and In Silico Studies

“…As shown in Figure 4 B, the IC 50 against EGFR-TK of VF16 is 7.85 ± 0.88 nM, which is significantly lower than the erlotinib (IC 50 of 26.09 ± 5.42 nM). Additionally, the inhibitory activity of VF16 is greater than that of the chalcones that have been previously reported to inhibit EGFR activity (IC 50 ranked from 10.3 to 15.4 µM) [ 25 ].…”

“…Vinyl sulfone (VF) is an organic compound, where its core structure is similar to that of chalcones [ 21 , 22 , 23 , 24 ] ( Figure 1 ). Previous study has shown that chalcone derivatives can inhibit EGFR activity with the IC 50 value ranged from 10.3–15.4 µM [ 25 ]. Thus, we hypothesized that VF derivatives can inhibit EGFR-TK activity in a manner similar to chalcones.…”

EEF1A2 and ERN2 could potentially discriminate metastatic status of mediastinal lymph node in lung adenocarcinomas harboring EGFR 19Del/L858R mutations

“…35 Furthermore, the equilibrium constant Ki of interaction between erlotinib and EGFR with 19Del mutation is far lower than that of EGFR with L858R mutation. 36 Wang et al revealed that EGFR protein with 19Del mutation exhibits lower degradation rate than EGFR protein with L858R mutation because of lower interaction with c-Cbl. 37 Second, from a clinical point of view, in a randomized controlled phase III clinical trial (EURTAC study) 16 that compared first-line EGFR TKI treatment with chemotherapy in advanced NSCLC, patients with different EGFR mutation types had different benefit extents from EGFR TKI.…”

“…has shown that the autophosphorylation site of EGFR with L858R mutation is different from that with 19Del mutation, and the tyrosine residues of the 845 code in EGFR with L858R mutation is highly phosphorylated which results in different downstream signaling pathways 35 . Furthermore, the equilibrium constant Ki of interaction between erlotinib and EGFR with 19Del mutation is far lower than that of EGFR with L858R mutation 36 . Wang et al .…”

Synthesis and evaluation of C3 substituted chalcone‐based derivatives of 7‐azaindole as protein kinase inhibitors

“…Chalcones have attracted considerable attention because of their promising therapeutic effects. Natural and synthetic chalcones have demonstrated a broad spectrum of therapeutic effects including antibacterial, antifungal, antiviral, anti‐inflammatory, antioxidant, and most importantly, anticancer activities (Sangpheak et al., 2019). According to Mphahlele, Maluleka, Parbhoo, and Malindisa (2018), chalcone‐based compounds have several mechanisms of action, among which are induction of apoptosis, DNA and mitochondrial damage, inhibition of angiogenesis and kinase inhibition.…”