Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries. The kinase activity of DNA-PK appears to be essential for DNA double strand break (DSB) repair and its inhibition has been shown to elicit chemo-sensitization by potentiating the cytotoxicity of DSB-inducing agents in vitro. Enormous research has been done exploring the possibilities of achieving a DNA-PK specific inhibitor and to date not many have been described. Since DNA-PK is a member of the phosphatidylinositol PI 3-kinase-like (PIKK) family, many of the reported compounds also inhibit other related phosphatidylinositol 3-kinases. Our study aims to elucidate the factors which contribute DNA-PK specificity thereby attaining a more selective and potent DNA-PK inhibitor. Here we describe the binding orientations and protein ligand interactions of substituted Benz 1, 3-oxazine derivatives in comparison to their biological activity against PI3K isoforms and DNA-PK. We report for the first time a relationship between the activity of these compounds against PI3K alpha isoform and their activity against DNA-PK inhibition.