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

D.      A. Sabbah; M.      G. Brattain; H.      Zhong

Abstract

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 PI3Kα 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.

Keywords: PI3Kα, mTORC1, mTORC2, kinase inhibitors, selectivity, rapamycin, cancer, phosphatidylinositol-3-kinase, chemotherapy, horizontal inhibition