D. A. Sabbah, M. G. Brattain and H. Zhong Pages 5528 - 5544 ( 17 )
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.
PI3Kα,mTORC1,mTORC2,kinase inhibitors,selectivity,rapamycin,cancer,phosphatidylinositol-3-kinase,chemotherapy,horizontal inhibition
, , DSC 362, Department of Chemistry, The University of Nebraska at Omaha, 6001 Dodge Street, Omaha, Nebraska 68182, USA.