Phosphatidylinositol 3-Kinase (PI 3-kinase) Inhibitors
The PI 3-kinases are ubiquitous, heterodimeric enzymes that play a pivotal role in the regulation of many cellular processes, including motility, proliferation, and survival, and carbohydrate metabolism. They are dual-specificity enzymes capable of phosphorylating phosphoinositides. PI 3-kinases are divided into three classes. Class I kinases were the first to be characterized and include receptor regulated heterodimeric enzymes consisting of a 110 kDa catalytic subunit and an 85 kDa regulatory subunit (p85/p110α; p85/p110β; p101/P110γ). They can use PI, PI (4)P, and PI (4,5)P2 as substrates in vitro. The major substrate in vivo appears to be PI(4,5)P2. The members of this class are sensitive to wortmannin. Class II PI 3-kinases can phosphorylate PI and PI(4)P in vitro and show variable responses to wortmannin. This class of enzymes contains a C-2 domain at the C-terminal region that binds phospholipids in a Ca2+-dependent manner. They participate in integrin signaling in platelets. Class III PI 3-kinases include Vps34 that can phosphorylate PI(3)P. The human homologue of Vps34 is reported to be sensitive to wortmannin and participates in the regulation of endocytic membrane trafficking. Activated PI 3-kinase phosphorylates phosphoinositol (PI) substrates to produce PI(3)P, PI(3,4)P2, and PI(3,4,5)P3. These molecules act as second messengers and recruit the PI 3-K-dependent serine/threonine kinases (PDK1) and Akt from the cytoplasm to the plasma membrane. Lipid binding and membrane translocation lead to conformational changes in Akt, which gets phosphorylated on Thr308 in the activation loop, and Ser473 in the hydrophobic phosphorylation motif by PDK1. This dual phosphorylation causes full activation of the enzyme. Inhibitors of PI 3-kinase and over-expression of dominant negative PI 3-kinase mutants are shown to block many of the physiological responses of a cell to insulin, indicating that PI 3-kinase lies upstream of these events. PI 3-kinase signaling is crucial to many aspects of cell growth and survival and this pathway is stimulated by many growth factors. Hence, PI 3-kinase activity is tightly regulated in normal cells. Abnormal activity of PI 3-kinase is seen in several forms of cancer. About 30% of solid tumors contain mutations in the catalytic subunit of PI 3-kinase. PI 3-kinase is becoming an attractive target for drug development, particularly in the areas of cancer and other proliferative diseases as well as in the treatment of inflammatory and immunological conditions.
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