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Akt Inhibitors and Selection Guide
 | | | | Akt (protein kinase B), a serine/threonine kinase, has emerged as a critical enzyme in several signal transduction pathways involved in cell proliferation, apoptosis, angiogenesis, and diabetes. In mammals three isoforms of Akt have been reported ( a , b , g or 1, 2, 3) that exhibit a high degree of homology, but 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 PIP2 to generate PIP3 (Figure 1). The binding of PIP3 to the PH domain anchors Akt to the plasma membrane and allows its phosphorylation and activation by 3-phosphoinositide-dependent kinase-1 (PDK1) (Figure 2). Akt is fully activated following its phosphorylation at two regulatory residues, a threonine residue on the kinase domain and a serine residue on the hydrophobic motif. The principal role of Akt is to facilitate growth factor-mediated cell survival and to block apoptotic cell death. Akt achieves this by phosphorylating a variety of substrates, such as Bad, caspase-9, and Forkhead transcription factors. High activity of Akt has been detected in many types of human cancers, hence it stands out as a valid molecular target in cancer chemotherapy. Most commercially available Akt inhibitors do not compete for the ATP-binding site. They act by either preventing the generation of PIP3 by PI-3 K or by blocking the binding of PIP3 to Akt. This inhibitory mode is utilized by the PI (phosphatidylinositol) analogs (Cat. No. 124005, 124008, 124009) and by a peptide derived from the proto-oncogene TCL1, which binds to the same region on the PH domain as PIP3 (Cat. No. 124013 and 124014). Another mode of inhibition is by preventing the activation of Akt via inhibition of upstream affectors. Akt Inhibitor IV (Cat. No. 124011) and Akt Inhibitor V, Triciribine (Cat. No. 124012) belong to this class of inhibitors. Akt Inhibitor IV is an ATP-competitive inhibitor of a kinase upstream of Akt, but downstream of PI-3 K whereas Akt Inhibitor V, Triciribine targets an Akt effector molecule other than PI-3 K or PDK1.
| | | | | | | | | | | | | | |  | | | Figure 1: Binding of PIP3 to the PH domain of Akt targets it to the membrane, where it is phosphorylated/activated by 3-phosphoinositide-dependent protein kinase-1 (PDK1). Most specific Akt inhibitors act by preventing its activation by blocking PIP3 production and/or binding. | | | | | | | | |
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| | | | | | | | | | | | |  | | | Figure 2: Structure of the pleckstrin homology (PH) domain of Akt bound to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). The PH domain is N-terminal to the Akt kinase domain, and binds PIP3 in a region that is positively charged. This may facilitate the binding of PH domain to the negatively charged plasma membrane when PIP3 is bound, anchoring Akt and allowing its phosphorylation by PDK1 | | | | | | | | |
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| | | | | | | Product | Cat. No. | Inhibits | Cell Permeable | Comments | Akt Inhibitor | | Akt, PI-3 K | Yes | PI analog, prevents PIP3 formation and binding to Akt (IC50 = 5.0 mM). For PI-3 K (IC50 = 83 mM) | | | | | | | Akt Inhibitor II (SH-5) | | Akt, PI-3 K | Yes | PI analog, prevents PIP3 formation and binding to Akt. Phosphonate analog, metabolically more stable than Akt Inhibitor, Cat. No. 124005. | | | | | | | Akt Inhibitor III (SH-6) | | Akt, PI-3 K | Yes | PI analog, prevents PIP3 formation and binding to Akt. Phosphonate analog, metabolically more stable than Akt Inhibitor, Cat. No. 124005. | | | | | | | Akt Inhibitor IV | | Akt | Yes | ATP-competitive inhibitor of a kinase upstream of Akt but downstream of PI-3 K. | | | | | | | InSolution™
Akt Inhibitor IV | | Akt | Yes | Supplied as a 10 mM solution of Akt Inhibitor IV (Cat. No. 124011) in DMSO. | | | | | | | | Akt Inhibitor IX, API-59CJ-OMe | | Akt | Yes | Induces apoptosis in human endometrial cancer cells (RL95-2 and Ishikawa) that exhibit elevated Akt activity (effective concentration = 12-24 mM), but not on cells with low Akt activity | | | | | | | Akt Inhibitor V, Triciribine
(API-2, NSC 154020, TCN) | | Akt | Yes | Inhibits the cellular phosphorylation/activation of Akt1/2/3 by targeting an Akt effector molecule other than PI-3 K or PDK1. Has shown efficacy in vivo. | | | | | | | Akt Inhibitor VI, Akt-in | | Akt | No | Peptide that binds to Akt-PH domain and interferes with the Akt-phosphoinositide interaction. | | | | | | | Akt Inhibitor VII, TAT-Akt-in | | Akt | Yes | Peptide that binds to Akt-PH domain and interferes with the Akt-phosphoinositide interaction. | | | | | | | Akt Inhibitor VIII, Isozyme-Selective, Akti-1/2 | | Akt | Yes | A cell-permeable quinoxaline compound that potently and selectively inhibits Akt1/Akt2 activity. | | | | | | | | Akt Inhibitor X | | Akt | Yes | Inhibits the phosphorylation of Akt and its in vitro kinase activity with minimal effect on PI 3-K, PDK1 and SGK1. | | | | | | |
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