2. Academic Validation
  3. Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier

Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier

  • Eur J Med Chem. 2022 Oct 5:240:114602. doi: 10.1016/j.ejmech.2022.114602.
Ram Sharma 1,  Esha Chatterjee 2,  Jacob Mathew 3,  Sachin Sharma 1,  N Vijayakameswara Rao 3,  Chun-Hsu Pan 4,  Sung-Bau Lee 5,  Ashwani Dhingra 6,  Ajmer S Grewal 6,  Jing Ping Liou 1,  Santosh K Guru 7,  Kunal Nepali 8
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan.
  • 2 Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, India.
  • 3 Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106335, Taiwan.
  • 4 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
  • 5 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan; Master Program in Clinical Genomics and Proteomics, College of Pharmacy, Taipei Medical University, Taiwan.
  • 6 Dept. of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Near Guru Nanak Khalsa College, Yamuna Nagar, 135001, Haryana, India.
  • 7 Department of Biological Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, India. Electronic address: santoshkumar.guru@niperhyd.ac.in.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan. Electronic address: nepali@tmu.edu.tw.
PMID: 35858522 DOI: 10.1016/j.ejmech.2022.114602
Abstract

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 μM) 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 nanoparticles) 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).

Keywords

Bronchodilator; Cancer; Cell growth; HDAC inhibitors; Hyaluronic acid (HA); Lung cancer; Nanoparticles (NPs); Scaffold; Tumor.

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