Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells

• Published in: European journal of medicinal chemistry 2020-10, Vol.203, p.112540, Article 112540
• Main Authors: Wu, Wei-Cheng, Liu, Yi-Min, Liao, Yu-Hsuan, Hsu, Kai-Cheng, Lien, Ssu-Ting, Chen, I-Chung, Lai, Mei-Jung, Li, Yu-Hsuan, Pan, Shiow-Lin, Chen, Mei-Chuan, Liou, Jing-Ping
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzamides - chemistry; Benzamides - pharmacology; Carcinoma, Non-Small-Cell Lung - pathology; Caspases - metabolism; Cell Line, Tumor; Colorectal cancer (CRC); Colorectal Neoplasms - pathology; Cytoprotection - drug effects; Enzyme Activation - drug effects; ErbB Receptors - metabolism; HSP90 inhibitors; Humans; Inhibitory Concentration 50; Lung Neoplasms - pathology; Mutation; Non-small cell lung cancer (NSCLC); Proteolysis - drug effects; Proto-Oncogene Proteins c-akt - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112540

A major cause of failure of therapy in patients with non-small cell lung cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC50 value of 27.8 ± 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BIIB021 whose IC50 values are 43.0 ± 0.9 nM and 56.8 ± 4.0 nM respectively. This strong HSP90 inhibitory activity of 12c leads to rapid degradation of client proteins EGFR and Akt in NSCLC cells. In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with apoptosis by showing activated caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for cancer treatment. [Display omitted] •Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamideshave be identified as HSP90 inhibitors.•Compound 12cdisplays potent HSP90α inhibitioncomparable to AUY-922 (Luminespib).•Compound 12cshows significant antiproliferative activity in CRC and NSCLCcells in a double digit nM range.•12cleads to rapid degradation of client proteins EGFR and Akt in NSCLC cells.•12cinduces significant accumulation of a sub-G1 phase population.