PI3K/Akt/mTOR inhibitor (PI3K/Akt/mTOR)

The phosphatidylinositol 3-kinase (PI3Ks) protein family is involved in the regulation of various cellular functions such as cell survival, growth, metabolism, and blood glucose homeostasis. Elevated PI3K kinase activity is often associated with a variety of cancers. As the name suggests, PI3Ks phosphorylates the third carbon atom of the inositol ring of the phosphatidylinositol PI (a membrane phospholipid). PI has a smaller proportion in the cell membrane fraction, less than phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine, but is abundant in the brain cell membrane, reaching 10% of the total amount of phospholipids. PI3K activation PI3K can be divided into three categories, with different structures and functions. The most widely studied of these is the class I PI3K, which is a heterodimer composed of a regulatory subunit and a catalytic subunit. The regulatory subunit contains the SH2 and SH3 domains and interacts with the target protein containing the corresponding binding site. This subunit is commonly referred to as p85, with reference to the first isotype found, whereas the six regulatory subunits currently known range in size from 50 to 110 kDa. There are four catalytic subunits, p110α, β, δ, γ, while δ is limited to white blood cells, and the rest are widely distributed in various cells. The activation of PI3K is largely involved in substrates near the inside of its plasma membrane. Multiple growth factors and signaling complexes, including fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), human growth factor (HGF), vascular protein I (Ang1), and insulin, all initiate PI3K Activation process. These factors activate the receptor tyrosine kinase (RTK), which causes autophosphorylation. The phosphorylated residue at the receptor provides a docking site for the heterodimerized PI3Kp85 subunit. In some cases, however, receptor phosphorylation mediates the recruitment of an adaptor protein. For example, when insulin activates its receptor, it must recruit an insulin receptor substrate protein (IRS) to promote PI3K binding. Similarly, when the integrin (non-RTK) is activated, focal adhesion kinase (FAK) acts as a adaptor protein, and PI3K is moored through its p85. However, in each of the above cases, the SH2 and SH3 domains of the p85 subunit bind to the adaptor protein at a phosphorylation site. Phosphorylation of various PI intermediates is initiated following recruitment of PI3K to the activated receptor. PI3K-transformed PIP2, which is particularly relevant to cancer, is PIP3. Activation of AKT The AKT activates cellular functions by phosphorylating downstream factors such as various enzymes, kinases, and transcription factors. For example, AKT stimulates glucose metabolism: AKT activates AS160 (AKT substrate, 160 kDa), which in turn promotes glucose uptake by GLUT4 transposition and myocytes. AKT also phosphorylates GSK3β to inhibit its activity, thereby promoting glucose metabolism and regulating cell cycle. AKT phosphorylates TSC1/2 (tuberous sclerosis complex), which prevents its negative regulation of Rab (Rs homology enriched in brain), which in turn leads to Rheb enrichment and rapamycin-sensitive mTOR complexes. Activation of (mTORC1). These effects activate protein translation and enhance cell growth. mTOR (mammalian rapamycin target protein) is a new member of the protein kinase family, which in turn belongs to the phosphatidylinositol kinase-associated kinase (PIKK). mTOR was discovered during the study of the immunosuppressant rapamycin. Scientists have found that the structurally similar immunosuppressive agents FK506 and rapamycin can bind to the same target protein FKBP12 (FK506 binding protein) to exert immunity. Inhibition, but it is different from the immunosuppressive mechanism of FK506. The complex formed by the binding of rapamycin to FKBP12 cannot bind to calmodulin, and rapamycin can not inhibit the early activation of T cells or directly reduce cytokines. The synthesis, which blocks signaling through different cytokine receptors, blocks the progression of T lymphocytes and other cells from G1 to S phase, while FK506 inhibits the proliferation of T lymphocytes from G0 to G1. . Due to the importance of mTOR in cell proliferation, differentiation, metastasis and survival, mTOR has become a new target in cancer therapy.