TOXICOLOGICAL STUDY ON THE EGFR PROTEIN INHIBITOR (IRESSA 1) USING TOPKAT

The epidermal growth factor receptor (EGFR) pathway has emerged as a key target in non-small-cell lung cancer. EGFR inhibition in non-small-cell lung cancer is achieved via small molecular tyrosine kinase inhibitors, such as erlotinib or Iressa (gefitinib), or monoclonal antibodies such as cetuximab. The EGFR is under investigation as a therapeutic target for cancers. Lung cancer cell lines are variably dependent on autocrine stimulation of EGFR since it has a role in signal transduction. We therefore examined the effects of a selective EGFR tyrosine kinase inhibitor Iressa 1 which is a synthetic molecule synthesized from a standard Iressa molecule. These compounds after docking with EGFR protein were found to possess good energy score and also highly inhibited the protein molecule indicating that this molecule showed anticancer activity on EGFR. The results of the pharmacokinetic study as well as the investigations pertaining to the ADME properties of  Iressa 1 by using ADME tool of TOPKAT (DS 2.5) had shown that Iressa 1  was nontoxic effect to female mouse and female rat (norms as per NTP carcinogenicity). Moreover, as per the FDA carcinogenicity value, it was found to be nontoxic to both male rat and male mouse. The pharmacokinetic results showed normal absorption rate, solubility, heptotoxicity, CYP2D6 and PPB values.