Novel benzoxazines as inhibitors of angiogenesis

In this study, we screened eight novel benzoxazine inhibitors of both PI3K isoforms and the related DNA-PK, for their anti-angiogenic effects. Our findings identified the novel benzoxazine (7, 8 (substituted)-2-morpholino-benz (1,3) oxazine: LTUSI122) to be non-toxic at concentrations up to 5 μM, while exhibiting significant inhibition of various aspects of angiogenesis including endothelial proliferation, migration and tube formation. The molecular mechanisms were examined using an angiogenesis array, revealing inhibition of several proliferative and migratory angiogenic factors, including VEGFR, MMP, IL-8, uPAR and MCP; and stimulation of the endogenous inhibitor, endostatin. We hypothesize that these anti-angiogenic effects are mediated by targeting an important signaling intermediary, PI3Kα, and subsequently its action on vascular endothelial growth factor (VEGF, a key growth factor in the process of angiogenesis). If used in combination with more targeted therapies, LTUSI122 could reduce tumour growth and increase the efficacy of these treatments.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research