Novel PI3K inhibitors and their antitumor mechanism

PI3K is a kind of lipid kinase, which is involved in the regulation of many cell biological processes (cell proliferation, growth, migration and metabolism) closely related to tumor development The abnormal activation of PI3K / mTOR signal pathway is closely related to tumor development and radiochemotherapy resistance Tumor stem cells are the root cause of tumor occurrence, recurrence and metastasis The latest research shows that PI3K / mTOR signaling pathway is involved in the regulation of tumor stem cells In-depth research on the regulation mechanism and the discovery of novel inhibitors targeting the signaling pathway are of great significance for tumor treatment Li Yan research group, natural product pharmacology and new drug creation team of Kunming Institute of Botany, Chinese Academy of Sciences, and Zhang Hongbin research group, Yunnan University, designed and synthesized a series of natural product libraries by using the methods of computer-aided drug design and pharmacophore heterozygosity Through the selection of kinase activity and antitumor activity in vitro, a series of novel furamidazole salts P were found B591, the representative compound of i3k inhibitor, can significantly inhibit the kinase activity of four subtypes of PI3K, and overcome the feedback activation of Akt and ERK caused by the inhibition of mTORC1, showing potential clinical value of antitumor Compared with ordinary tumor cells, B591 significantly inhibited the self-renewal of tumor stem cells By targeting tumor stem cells, B591 can effectively inhibit the lung metastasis of breast cancer cells in mice, and significantly inhibit the recurrence of breast cancer after chemotherapy with paclitaxel This study laid a solid foundation for the research and development of PI3K kinase inhibitor as an anti-tumor drug targeting tumor stem cells This research achievement was published in the international Tumor Research Institute under the title of B591, a new specific pan-PI3K inhibitor, preferred targets cancer stem cells Zhou Hongyu, associate researcher of Kunming Institute of Botany, born in Chunlei, Ph.D., and Kong Lingmei, assistant researcher are the co authors, Li Yan, researcher of Kunming Institute of Botany, Zhang Hongbin, Professor of Yunnan University, and Yang Xiaodong are the co authors The research was supported by the National Natural Science Foundation of China (u140222721662043), the Yangtze River scholars and innovation team development plan of the Ministry of Education (irt17r94), etc