PI3K/Akt/mTOR

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway that regulates cell cycle proliferation, growth, survival, protein synthesis, and glucose metabolism. The PI3K/Akt/mTOR pathway is activated by growth factors (e.g., IGF-1 and insulin) and has a number of downstream effects which either promote protein synthesis or inhibit protein breakdown. Components of the PI3K/Akt/mTOR pathway are frequently abnormal in a variety of tumors, especially breast cancer and non-small-cell-lung cancer, making them an attractive target for anti-cancer therapy.^[1] Class I PI3Ks are comprised of two subunits, a regulatory subunit (p85α, p85β, and p55γ) and a p110 isoform (p110α, β, γ, and δ). The first generation PI3K inhibitors were based upon LY294002 and wortmannin, inhibiting the catalytic p110 subunit. ZSTK474, XL147, GDC-0941 are all selective PIK inhibitors with PI3K-isoform selectivity.^[2] AKT is a protein serine/ threonine-specific kinase and has three members, termed AKT 1(PKBα), AKT 2 (PKBβ), and AKT 3 (PKBγ). There are several chemical classes of small-molecule AKT inhibitors with varying potencies and specificities for the different AKT isoforms, including phosphatidylinositol analogs, ATP-competitive small molecules, pseudosubstrate compounds, and allosteric inhibitors.^[3] Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase in the PI3K cascade and plays critical roles in the regulation of cell growth, survival, division, and motility. mTOR acts through two separate complexes mTORC1 and mTORC2. The most extensively studied mTOR inhibitors are rapamycin and its analogues RAD-001 (everolimus), CCI-779 (temsirolimus), and AP23573 (deforolimus).^[4]

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