Preclinical Study Of Puquitinib, A Novel Orally Available Pi3k Inhibitor In Phase I Clinical Trials

Extensive evidence implicates activation of PI3K pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. In this report, we detailed the pharmacologic properties of puquitinib, a novel orally available PI3K inhibitor structurally distinct from all those known so far. Puquitinib reduced the levels of phosphatidylinositol-3,4,5-trisphosphate (PIP3), a product of PI3K, and inhibited the phosphorylation, translocation and membrane ruffling of AKT, the signaling component downstream from PI3K. The inhibitory effects of puquitinib on PI3K signaling were correlated with its potent anti-proliferative activity in a panel of tumor cells. Puquitinib also demonstrated potent anti-angiogenic effects in the tubule formation and cell migration assays of human umbilical vein endothelial cells, and micro-vessel spouting from matrigel-embedded rat aortic rings. Oral administration of puquitinib showed strong antitumor activity in various human cancer xenograft models without any noticeable toxicity, along with the reduction of phosphorylated AKT in tumor tissues. Collectively, the preclinical data show that puquitinib is a potent PI3K inhibitor with favorable pharmaceutical properties. Puquitinib is currently being evaluated in phase I clinical trials in China. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4245. doi:10.1158/1538-7445.AM2011-4245