Akt (Protein Kinase B) Inhibitors

Akt, also known as protein kinase B (PKB), a serine/ threonine kinase, is a critical enzyme in several signal transduction pathways involved in cell proliferation, apoptosis, angiogenesis, and diabetes. Four different isoforms of Akt (a, b1, b2, and g) have been reported that differ slightly in the localization of their regulatory phosphorylation sites. Activation of Akt involves growth factor binding to a receptor tyrosine kinase and activation of PI 3-K, which phosphorylates the membrane bound PI (4,5)P2 (PIP2) to generate PI(3,4,5)P3 (PIP3). Binding of PIP3 to Akt anchors it to the plasma membrane and exposes it to phosphorylation and activation by 3-phosphoinositidedependent kinase-1 (PDK1). Akt is activated following its phosphorylation at two regulatory residues, a threonine residue on the kinase domain and a serine residue on the hydrophobic motif, which are structurally and functionally conserved within the AGC kinase family. Phosphorylation of threonine on the kinase domain, catalyzed by PDK1, is essential for Akt activation. Akt activity is augmented approximately 10-fold by phosphorylation at the serine on the hydrophobic motif by PDK2. Phosphorylation of Thr308 and Ser473 activates Akt a. Phosphorylation at Thr309 and Ser474 on Akt b1 and b2, and on Thr305 on Akt g result in their activation. The activation of Akt is negatively regulated by PTEN, a PIP3 specific phosphatase, and SHIP, an SH2-domain containing inositol 5-phosphatase.

The identification of Akt as a key regulator of cellular survival has significant implications for oncogenesis. A number of oncogenes and tumor suppressor genes that function upstream of Akt influence cancer progression by regulating Akt. The principal role of Akt in the cell is to facilitate growth factor-mediated cell survival and to block apoptotic cell death. This is achieved by phosphorylating and deactivating pro-apoptotic factors such as BAD, Caspase-9, and Forkhead transcription factors (FKHR). The phosphorylation of BAD allows it to bind to 14-3-3 protein thereby preventing localization of BAD at the mitochondria to induce apoptosis. Additionally, phosphorylation of FKHR by Akt prevents it from inducing expression of Fas ligand; hence it promotes cell survival. Akt also phosphorylates and activates IKKa, which leads to NF-kB activation and cell survival. Akt is also known to stimulate glycogen synthesis by phosphorylating and inactivating GSK-3 leading to the activation of glycogen synthase. The inactivation of GSK-3 also induces the up-regulation of cyclin D, which enhances cell cycle progression. Akt is reported to play a critical role in tumorigenesis, becoming activated when tumor suppressors such as p27Kip1 and PTEN lose their functions. Phosphorylation of p27 at Thr157 by Akt impairs its nuclear import and leads to its cytoplasmic accumulation. Cytoplasmic mislocalization of p27 has been strongly linked to loss of differentiation and poor outcome in breast cancer patients. Akt can also physically associate with endogenous p21, a cell cycle inhibitor, and phosphorylate it at Thr145, causing its localization to the cytoplasm, ultimately resulting in deregulation of cell proliferation.

References:
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Highlighted below are inhibitors included in InhiibtorSelect™ Akt/PI 3-K/mTor Signaling Pathway Inhibitor Panel