34P - Discovery of 1,3,5-triazine-monastrol based novel EGFR-tyrosine kinase inhibitor against human lung carcinoma

Date 07 May 2017
Event ELCC 2017
Session Poster Display Session
Topics Thoracic malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Udaya Singh
Citation Annals of Oncology (2017) 28 (suppl_2): ii9-ii13. 10.1093/annonc/mdx089
Authors U.P. Singh1, J.K. Shrivastava1, A. Verma1, H.R. Bhat2
  • 1Department Of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, 211007 - Allahabad/IN
  • 2Department Of Pharmaceutical Sciences, Dibrugarh University, 786004 - Dibrugarh/IN

Abstract

Background

In India, the number of new lung cancer cases has been increased with an annual rise of 15-20%. This poses a significant burden on already struggling healthcare services of the country. Thus, more efforts have been directed towards the easy access of the medicines and development of novel cost effective drug for the under-privileged. Consequently, introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in non-small cell lung cancer (NSCLC). However, resistance to these inhibitors either via intrinsic and acquired resistance, put a selective pressure on the development of novel inhibitors. Therefore, the present study was aimed to develop novel 1,3,5-triazine derivatives as EGFR-TKIs for lung carcinoma.

Methods

The 1,3,5-triazine-monastrol compounds were synthesized via multi-component reaction. The compounds were tested for determination of anticancer activity three human NSCLC cell lines A549, H157 and H52. The compounds were also tested for effect on cell growth inhibition and apoptosis through cell cycle arrest assay. The docking analysis was also carried out with EGFR-TK domain (PDB ID: 1M17) to elucidate vital structural residues necessary for bioactivity.

Results

The cytotoxicity studies results suggest that, synthesized derivatives exhibit considerable inhibition with average IC50 for compound 7a were found to be 3.21, 6.32 and 11.05 µmol/l. It has been found that, 7h showed augmention in the number of cells in G0–G1 phase, with a subsequent decrease in the cells belonging to S and G2–M phase. It also causes modulation of tumor cell apoptosis in a concentration-dependent way. In docking study, it has been found that, compound 7h, 7l, 7m, 7e were found to be the most efficient analogues to attenuate EGFR-TKs via creating MET769, ASP831, LYS721 and CYS773 amino acids comparable to erlotinib.

Conclusions

In conclusion, 1,3,5-triazines-monstrol conjugates has shown promising antitumor activity via inhibition EGFR-TK in lung carcinoma and my find serve as a lead for further research.

Clinical trial identification

Legal entity responsible for the study

SHUATS

Funding

SHUATS

Disclosure

All authors have declared no conflicts of interest.