Cancer

In vitro, cell culture and mouse studies identified four methylquinazoline-based PI3K inhibitors that could help treat cancer. Chemical synthesis of methylquinazoline analogs and in vitro enzyme activity assays yielded four compounds that inhibited PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ with IC₅₀ values of 0.18-1.7 nM. In a panel of 10 human cancer cell lines, the compounds were cytotoxic with IC₅₀ values of 25 nM to 6.5 µM. In mice, two of the compounds had greater area under the curve (AUC) for brain concentration-time plots than the other two compounds. In xenograft mouse models of gastric cancer and non-small cell lung cancer (NSCLC), the two compounds with low brain exposure decreased tumor growth compared with vehicle. In another xenograft mouse model of gastric cancer and an orthotopic xenograft mouse model of glioma, the two compounds with high brain exposure decreased tumor growth with potencies comparable to temozolomide. Next steps could include optimizing and testing the compounds in additional models of cancer...