الفهرس 
English SummaryOnly 14 pages are availabe for public view
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Abstract
The introduction of molecularly targeted agents in cancer therapy has achieved impressive results. The HGF/ c-Met axis offers potentially high-value target for cancer drug development. The preliminary data obtained with several HGF/ c-Met targeted agents are obviously supportive of the strong involvement of dysfunctional HGF/ c-Met signaling in human cancers. Among the different strategies for targeting the HGF/ c-Met pathway, smallmolecule kinase inhibitors have attracted significant attention and several inhibitors are entering late-stage clinical studies.
Remarkably, in the past several years, 1,2,4-triazines have proved to possess excellent c-Met kinase inhibitory activity as well as an impressive array of biological activities especially antitumor properties.
The present research work aimed at the design, synthesis and antitumor evaluation of new 1,2,4-triazine derivatives as c-Met kinase inhibitors with the hope of discovering new potential antitumor leads.
The present thesis comprises the following chapters: Chapter One: Introduction This chapter comprises a concise survey on the recent literature describing the structure and function of c-Met kinase enzyme as well as its role during tumor formation and progression together with the different types of reported c-Met kinase inhibitors in phase I-III clinical trials. More focus was shed on 1,2,4-triazines possessing c-Met kinase inhibitory activity as well as recent literature reports on 1,2,4-triazine derivatives as antitumor agents. Chapter Two: Research Objectives This chapter deals with aim of the work and the outlined research strategy which relies upon the obtained results of our previously synthesized and NCI-tested compound NCI 748494/1.
Chapter Three: Target Identification and Lead Optimization This chapter describes the application of target fishing approach using PharmMapper server which led to identifying c-Met kinase enzyme as the potential protein target for the antitumor agent NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase enzyme. Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead. Based on target identification and validation, it was observed that there is a structure similarity between NCI 748494/1 and the reported type II c-Met kinase inhibitors. Therefore, several optimization strategies of the lead NCI 748494/1 were followed in order to develop new potent antitumor 1,2,4-triazine derivatives as c-Met kinase inhibitors.