Inhibition of tumour angiogenesis, as a means of reducing the growth of cancers, has become a promising target for adjuvant therapies. Angiogenesis begins with the proliferation of endothelial cells, followed by their migration and structural reorganisation into tubular structures, which align to form the new blood vessel. The DNA-PK and PI3K inhibitors LY249002 and its newer derivative NU7026 have been found to have anti-angiogenic effects on endothelial cells by inhibiting proliferation and tube formation (1). This study utilise the endothelial cell line (HUVECs) and novel benzoxazine analogues of LY294002, to determine if they have similar anti-angiogenic effects on endothelial cells with less toxic side effects. Eight benzoxazines have been developed with varying inhibitory potencies against the PI3K isoforms and DNA-PK. Toxicity prolife of the eight compounds revealed LTUSI58 was the only compound found to be toxic at concentrations up to 5μM. With the elimination of toxic compound LTUSI58 from any further testing, the effect on the angiogenic processes: proliferation, migration and tube formation of HUVECs at various compound concentrations was examined. The effect on proliferation (SRB assay) identified LTUSI122 as having a significant inhibitory effect. The compound also showed significant inhibition of migration, determined using both the ‘scratch assay’ and the Boyden’s chamber. To determine the effect on tube formation, cells were cultured on growth ECM (Geltrex). After 18 hours in culture the number of complete tubes formed was counted as a measure of tube formation. The inhibitory effect of LTUSI122 continued resulting in less tubes being formed. The molecular mechanisms were examined using an angiogenesis array, revealing inhibition of several proliferative and migratory factors, including VEGFR, MMP, IL-8, UPR and MCP. LTUSI122 also stimulated the endogenous inhibitor, endostatin. Our findings indicate that the benzoxazine, LTUSI122, is a potent inhibitor of several aspects of the angiogenic process, through its inhibition of PI3Kα, which used in combination with more targeted therapies, could reduce tumour growth and increase the efficacy of these treatments.