Introduction Cancer is known as a

Introduction Cancer is known as a renegade system of expansion that initiate in human body. It is distinguished, in spite of its category, by one universal characteristic, which is uncontrolled cell division. Cancerous 2-D08 have the ability to bypass the normal apoptosis mechanism (National Cancer Institute, 2012). According to the World Health Organization [WHO] 8.2 million cancer deaths were reported in 2012 worldwide and the figure is likely to expand by 70% in the year 2030. In fact, one third of the deaths are related to five main risk factors which include obesity, lack of exercise, low vegetables and fruit diet, smoking and alcohol use. Smoking causes about 20% of total cancer deaths and around 70% of total lung cancer deaths worldwide. In Eastern Mediterranean Region, cancer can kill more than quarter a million people each year (Jemal et al., 2011; World Health Organization (WHO), 2012). A great investment and enormous efforts have been made to treat cancer, which have been effectively contributed to a decline in the mortality rate. However, many reasons prohibit the discovery of the optimal cure including the unique characteristics of each cancer, different response to treatment and most importantly, the lack of selectivity where treatment cannot be directly focused toward cancerous cells and avoiding the normal tissues. Therefore, the demand to find a new valid target for cancer therapy is increasing (Aziz and Rowland, 2003; Petrelli et al., 2009). The Glyoxalase system, particularly Glo-I, has received a particular interest by researchers in the last decades as a valid target for the development of new anticancer agents. The Glyoxalase structure consist of two enzymes Glyoxalase I (Glo-I) and Glyoxalase II (Glo-II) where they both act as a detoxification tool of the toxic byproducts such as methylglyoxal (MG) that are generated during the normal metabolic pathway including glycolysis. The Glo-I catalyses the isomerization of hemithioacetal substrate, nonenzymatically formed by reaction of MG and glutathione (GSH), into S,D-lactoylglutathione which is a substrate for Glo-II that hydrolyzes the thioester into less toxic D-lactic acid (Davidson et al., 2002; Rabbani and Thornalley, 2011; Thornalley and Rabbani, 2011; Xue et al., 2011). Glyoxalase system is found in regular and malignant cells with much greater expression rate in the cancerous cell as the metabolic rate and hence the toxic metabolites are higher. Beside, the overexpression of the Glo-I has been linked to the resistance of the tumour cells to chemotheraputic agents (Sakamoto et al., 2000; National Toxicolog and y Program, 2010; Chaplen, 1998; Suttisansanee and Honek, 2011). Scientists have anticipated that the inhibition of the Glo-I and Glo-II will subsequently accumulate the noxious metabolites including MG which leads to the degeneration of the cancerous cells (Feierberg et al., 2000; Thornalley, 2003b, a). Therefore, Glo-I has attracted the attention of researchers worldwide as a decisive target in the discovery of new anti-cancer agents (Al-Balas et al., 2016, Al-Balas et al., 2019). These extensive efforts has resulted in identifying novel potential inhibitors of Glo-I based on customized pharmacophore possessing a zinc chelating group (Al-Balas et al., 2012). Recent studies have successfully identified new Glo-I inhibitors by implementing different approaches such as high-throughput screening (Yadav et al., 2016), structure-based design (More and Vince, 2007), and pharmacophore-based models (Al-Shar’I et al., 2015). Our research group recently reported the utilization of inventive approach towards the discovery of new inhibitory leads against heat shock protein 90 (Hsp90) (Al-Sha'er et al., 2016) and Akt1 (Al-Sha'er et al., 2015). This method depends on co-crystallized protein structure to generate a series of pharmacophores that have been evaluated using QSAR anaylsis, followed by ROC analysis, then the best model is used as a searching tool for the NCI database.