Dual Inhibitors of PI3K/mTOR or mTOR-Selective Inhibitors: Which Way Shall We Go?

作者：Sabbah D A; Brattain M G; Zhong H^*

来源：Current Medicinal Chemistry, 2011, 18(36): 5528-5544.

DOI：10.2174/092986711798347298

• PI3K alpha
• mTORC1
• mTORC2
• kinase inhibitors
• selectivity
• rapamycin
• cancer

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway is a central regulator in cell proliferation, growth, and angiogenesis. Inhibition of this pathway therefore is a major strategy for cancer chemotherapy. In order to induce the maximal therapeutic outcome in cancer treatment, vertical inhibition of the PI3K/AKT/mTOR pathway or horizontal inhibition of PI3K/AKT/mTOR and other kinases has been reported. In this review, we discuss the drug design and clinical development of dual inhibitors of PI3K and mTOR as well as the mTOR-selective inhibitors, classified based on the mechanism of action and the chemical structures. Structural determinants for increasing selectivity toward PI3K alpha or mTOR are revealed from the structure-activity relationship of the reported inhibitors. Current clinical development in combination therapy of inhibitors involving in the PI3K/AKT/mTOR pathway is also discussed.

• 出版日期2011-12