Identification of antiproliferative nogalamycin series as potent inhibitors of EGFR tyrosine kinase: An in vitro and computational study.

Following from our previous discovery of NSC116555 (nogalamycin N-oxide) as an EGFR-TK inhibitor leads to this study which further expands the research scope of the nogalamycin series as inhibitors of EGFR-TK. In this study, a similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structurally-related molecules to NSC116555. Six additional molecules of the same series were available, obtained and biologically evaluated. NSC265450 and NSC70845 were the most potent antiproliferative agents with IC50 < 4 nM against overexpressed EGFR-TK cancer cell lines, HeLa and A549, displayed significantly much greater potencies than NSC116555, erlotinib and doxorubicin. EGFR-TK inhibition results revealed NSC70845 was the most potent of the series with an IC50 value of 15.48 nM, approximately twice more potent than NSC116555. Additionally, evaluation results were highly promising for the series against multi-drug resistant H69AR small cell lung cancer, and MDA-MB-231 triple-negative breast cancer cells exhibiting IC50 values as potent as 5 nM and 510 nM, respectively. Induction of apoptosis and reduced AKT phosphorylation was clearly evident for the most active molecule, NSC70845. Furthermore, molecular docking and molecular dynamics results predicted the binding action of the series to the ATP binding site of EGFR-TK; intermolecular interactions to key regions of the protein and amino acid residues are described. Prediction of pharmacokinetic and toxicity profiles of the series, and calculations of known drug indexes suggest the molecules are pharmaceutically compatible as therapeutic drug candidates.