Quantitative Structure Activity Relationship ...

Quantitative Structure Activity Relationship Based Molecular Modeling of EGFR tyrosine kinase inhibitor

Author Name : Dr. Ranjana

ABSTRACT

Non small celllung cancer  is (NSCLC) one of the important causes of cancer mortality globally. There are three common types of non-small cell lung cancer (NSCLC)¹. Aden carcinomas ,Squamous cell carcinomas and Large cell carcinomas. Aden carcinomas are found in an outer area of the lung,  Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus) and Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types. One of the most important strategies for the treatment of NSCLC is to target the  Epidermal growth factor receptor (EGFR). Epidermal growth factor receptor (EGFR) belongs to the erbB family of receptor tyrosine kinases (RTKs). Tyrosine kinases are an especially important targetbecause they play an important role in the modulation of growth factor signaling. They compete with the ATP binding siteof the catalytic domain of several oncogenic tyrosine kinases.²They are orally active, small molecules that have a favorablesafety profile and can be easily combined with other forms ofchemotherapy or radiation therapy. Several tyrosine kinase inhibitors(TKIs) have been found to have effective antitumoractivity and have been approved or are in clinical trials.

Tyrosine kinases play a critical role in the modulation of growth factor signaling³. Activated forms of these enzymes can cause increases in tumor cell proliferation and growth, induce antiapoptotic effects, and promote angiogenesis and metastasis. In addition to activation by growth factors, protein kinase activation by somatic mutation is a common mechanism of tumor genesis. Because all of these effects are initiated by receptor tyrosine kinase activation, they are key targets for inhibitors. In this series the role of  4-anilinotetrahydropyrido[4,3-d] pyrimidine was investigated by Yong Zhang and coworkers.⁴  The present work deals with the QSAR studies on substituted pyrimidines against the H1975 cell line and the activity  data as reported by them has been used.

It is hoped that this study will produce models that can be used for future designing of new analogues with higher potency. Inhibitory activity pIC₅₀ expressing the antiproliferative activities against the H1975 cells are reported in literature, where  pIC₅₀ represents the inhibition of the binding of receptor to the receptor site.

Hansch analysis^14-20 has been used for mono and Multiparametric regression analysis^21-23Pogliani 's quality factor^24,25  and other statistical techniques for investigating the predictive power of various parameters were used and finally cross validation technique^26,27  was employed to test the validity of models. The regression analysis used to derive the correlation was executed with SPSS 7.5 Software²⁸

The different analogues of  parent structure and values of biological activity are reported in table 5-3.1