Background: We previously reported on the design and synthesis of novel azatyrosinamide derivatives selective for ras-transformed NIH3T3 cells and with improved toxicity over azatyrosine. This study was aimed at investigating the mechanism of action and the antitumour activity of these compounds in ras-transformed cells. Materials and Methods: Nine azatyrosinamides were previously screened for anticancer activity in both wild-type and ras-transformed NIH3T3 cells; the most active compounds were further tested in vitro and in vivo. Results: HPW98-1 and HPW98-2 induced formation of apoptotic bodies in ras-transformed NIH3T3 cells in vitro and inhibited anchorage-independent growth. Excess tyrosine reduced the cytotoxic effect of azatyrosine, but not of HPW98-1 and HPW98-2. HPW98-1 reduced vascular endothelial growth factor-mediated angiogenesis in a Matrigel plug assay and attenuated growth of a ras-transformed NIH3T3 xenograft and a human SW620 xenograft. Conclusion: Our results support the continued study of HPW98-1 for its potential use in the treatment of RAS-related cancers.
