6P - Design, synthesis and evaluation of Hybrid of Quinazoline –triazine derivatives as FAK inhibitor with antitumor activity (6P)

Date 18 November 2017
Event ESMO Asia 2017 Congress
Session Poster lunch
Topics Basic Science
Presenter Amita Verma
Citation Annals of Oncology (2017) 28 (suppl_10): x1-x6. 10.1093/annonc/mdx652
Authors A. Verma1, V. Kumar1, P. Pathak1, P.K. Shukla1, A. Kumar2, U.P. Singh1, A.K. Singh3
  • 1Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, 211007 - Allahabad/IN
  • 2Pharmaceutical Sciences, S. V. Subharti University, Meerut/IN
  • 3Ent, ESIC Hospital, Varanasi/IN

Abstract

Background

Focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase and scaffold protein localized to focal adhesions, is uniquely positioned at the convergence point of integrin and receptor tyrosine kinase signal transduction pathways. Amplified expression of FAK is found in a variety of human cancers. Evidence supports the idea that FAK appearance in endothelial cells is necessary for the construction of new blood vessels and for the endurance of endothelial cells. Overexpression of FAK in vascular endothelial cells directly promotes angiogenesis in transgenic mice. Taking this as a prime consideration we developed hybrid of quinazoline-triazine derivatives (QTD) as a potential inhibitor of FAK for anti-cancer activity.

Methods

Designing of (QTD) was done according to molecular field mapping and alignment parameters via comparison analysis through standard angiogenic inhibitor vandetanib. Docking calculations were performed by Auto dock 4.2 for most significant comparable designed derivatives on FAK protein (PDB ID: 2ETM). QTD were synthesized through a cost-effective synthetic approach. The derivatives were evaluated for in vitro anti-cancer activity on two different cell lines, MCF-7 (Breast Carcinoma) and TPC-1 (Human Thyroid carcinoma). Further in ovo angiogenic inhibition was performed on chick embryo through CAM assay.

Results

All the designed derivatives expressed more than 50% field similarity and their atomic field conjugations. Docking studies revealed significant results compared with standard drug. The 8d showed interaction with ILE428, CYS502, and LEU501 residue of protein fragment. In terms of activity IC50 report clearly marked that selected QTD have significant proliferative inhibition against a variety of cancer cell lines, and in ovo results explored that derivatives are non-toxic to normal cells as well as significantly active against cancer induced chick embryo.

Conclusions

It has been concluded that QTD could serve as a lead for future drug discovery in cancer therapy because of significant anticancer effect via inhibition of FAK and antiangiogenic effect.

Clinical trial identification

NA

Legal entity responsible for the study

N/A

Funding

None

Disclosure

All authors have declared no conflicts of interest.