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.
Original language | English (US) |
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Pages (from-to) | 5528-5544 |
Number of pages | 17 |
Journal | Current medicinal chemistry |
Volume | 18 |
Issue number | 36 |
DOIs | |
State | Published - Dec 2011 |
Keywords
- And cancer
- Kinase inhibitors
- PI3Kα
- Rapamycin
- Selectivity
- mTORC1
- mTORC2
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Pharmacology
- Drug Discovery
- Organic Chemistry