期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 240, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114602
关键词
HDAC inhibitors; Lung cancer; Cancer; Tumor; Cell growth; Bronchodilator; Scaffold; Hyaluronic acid (HA); Nanoparticles (NPs)
资金
- Ministry of Science and Tech- nology, Taiwan [MOST 111-2320-B-038 -047-, 110-2320- B-038-028]
A suitable fragment was selected and incorporated into the HDAC inhibitory template to develop potential lung cancer treatment drugs through a fragment recruitment process. Compound 6, a fused quinazolinone, exhibited potent anticancer activity against KRAS and EGFR mutant lung cancer cell lines. Mechanistic studies revealed that compound 6 inhibited the activity of HDAC6, HDAC1, and HDAC3, leading to cell growth inhibition, apoptosis induction, and increased autophagic flux. Furthermore, a pH-responsive nanocarrier showed selective cytotoxicity against lung cancer cells under acidic conditions.
A fragment recruitment process was conducted to pinpoint a suitable fragment for installation in the HDAC inhibitory template to furnish agents endowed with the potential to treat lung cancer. Resultantly, Ring C expanded deoxyvasicinone was selected as an appropriate surface recognition part that was accommodated in the HDAC three-component model. Delightfully, fused quinazolinone 6 demonstrating a magnificent anticancer profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80-0.96 mu M) was identified. Results of the mechanistic studies confirmed that the cell growth inhibitory effects of compound 6 stems for HDAC6 (IC50 = 12.9 nM), HDAC1 (IC50 = 49.9 nM) and HDAC3 inhibition (IC50 = 68.5 nM), respectively. Compound 6 also suppressed the colony formation ability of A549 cells, induced apoptosis, and increased autophagic flux. Key interactions of HDAC inhibitor 6 within the active site of HDAC isoforms were figured out through molecular modeling studies. Furthermore, a pH-responsive nanocarrier (Hyaluronic acid -fused quinazolinone 6 nano -particles) was designed and assessed using a dialysis bag approach under both normal and acidic circumstances that confirmed the pH-sensitive nature of NPs. Delightfully, the nanoparticles demonstrated selective cell viability reduction potential towards the lung cancer cell lines (A549 lung cancer cell lines) and were found to be largely devoid of cell growth inhibitory effects under normal settings (L929, mouse fibroblast cells).
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