Figure 3.

Ipatasertib mechanism of action. PI3K /AKT signaling pathway. Several types of cancers are characterized by dysregulation of the PI3K (phosphatidylinositol 3-kinase)/AKT (or PKB, protein kinase B) signaling pathway, which is involved in the regulation of multiple cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. The PI3K/AKT pathway starts from stimulation of Receptor Tyrosine Kinase (RTK). When signaling molecules bind to the RTK extracellular ligand binding domain (1), two RTK monomers get close and form a cross-linked dimer (2). Cross-linking activates the intracellular tyrosine kinase domains (TKDs) and each RTK monomer phosphorylates multiple tyrosines on the other RTK monomer (3). These phosphotyrosine residues serve as recruitment sites for several downstream signaling proteins, which lead to PI3K phosphorylation and activation (4). PI3K mediates the conversion of PIP2 into PIP3 (5), which, together with activating kinases, leads to the phosphorylation and activation (6) of AKT. AKT is the central node of the pathway and its downstream signaling controls many key cellular activities (7). The PI3K/AKT pathway is tightly regulated by the tumor suppressor PTEN (8), through its ability to dephosphorylate and inhibit PIP3. In many cancers are present alterations in the genes that encode key proteins of the pathway (including PTEN, PI3K and AKT), leading to hyperactivation of AKT signaling. This hyperactivation promotes uncontrolled cell growth. Ipatasertib can inhibit AKT by binding to the ATP-binding pocket (9), leading to inhibition of downstream signaling. Thus, ipatasertib reduces cell growth and proliferation.