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 (&alpha , β ,γ 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.
References:
Castillo, S.S. et al. 2004. Cancer Res. 64, 2782.
Hiromura, M., et al. 2004. J. Biol. Chem. 279, 53407.
Yang, L., et al. 2004. Cancer Res. 64, 4394.
Bain, J. et al. 2003. Biochem J. 371, 199-204.
Kau, T.R., et al. 2003. Cancer Cell 4, 463.
Kozikowski, A.P., et al. 2003. J. Am. Chem. Soc. 125, 1144.
Davies, S.P., et al. 2000. Biochem J. 351, 95-105.
Hu, Y., et al. 2000 J. Med. Chem. 43, 3045.
Thomas, C. C., et al. 2002. Curr.Biol. 12, 1256.
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Product
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Cat. No.
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Inhibits
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Cell Permeable
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Comments
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|---|---|---|---|---|
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InhibitorSelect™ Akt/PI 3-K/mTOR Pathway Inhibitor Panel
|
See Data Sheet
|
Yes
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A panel of 12 highly potent and selective kinase inhibitors and a negative control useful for the study of Akt/PI 3-K/mTOR signaling pathway. | |
|
Akt Inhibitor
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Akt, PI-3 K
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Yes
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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
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Yes
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PI analog, prevents PIP3 formation and binding to Akt. Phosphonate analog, metabolically more stable than Akt Inhibitor, Cat. No. 124005. | |
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Akt Inhibitor III (SH-6)
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Akt, PI-3 K
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Yes
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PI analog, prevents PIP3 formation and binding to Akt. Phosphonate analog, metabolically more stable than Akt Inhibitor, Cat. No. 124005. | |
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Akt Inhibitor IV
|
Akt
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Yes
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ATP-competitive inhibitor of a kinase upstream of Akt but downstream of PI-3 K. | |
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InSolution™
Akt Inhibitor IV |
Akt
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Yes
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Supplied as a 10 mM solution of Akt Inhibitor IV (Cat. No. 124011) in DMSO. | |
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Akt Inhibitor V, Triciribine
(API-2, NSC 154020, TCN) |
Akt
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Yes
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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. | |
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Akt Inhibitor VI, Akt-in
|
Akt
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No
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Peptide that binds to Akt-PH domain and interferes with the Akt-phosphoinositide interaction. | |
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Akt Inhibitor VII, TAT-Akt-in
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Akt
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Yes
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Peptide that binds to Akt-PH domain and interferes with the Akt-phosphoinositide interaction. | |
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Akt Inhibitor VIII, Isozyme-Selective, Akti-1/2
|
Akt
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Yes
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A cell-permeable quinoxaline compound that potently and selectively inhibits Akt1/Akt2 activity. | |
| InSolution™ Akt Inhibitor VIII, Isozyme-Selective, Akti-1/2 |
Akt
|
Yes
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A 10 mM solution of Akt Inhibitor VIII, Isozyme-Selective, Akti-1/2 (Cat. No. 124018) in DMSO. | |
| Akt Inhibitor IX, API-59CJ-OMe |
Akt
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Yes
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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 X |
Akt
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Yes
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Inhibits the phosphorylation of Akt and its in vitro kinase activity with minimal effect on PI 3-K, PDK1 and SGK1. | |
| Akt Inhibitor XI |
Akt
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Yes
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Interacts with both the PH and the kinase domains of Akt and potently inhibits its kinase activity (IC50 = 100 nM). | |
| Akt Inhibitor XII, Isozyme-Selective, Akti-2 |
Akt
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Yes
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An Akti-1/2- (Cat. No. 124018) derived allosteric inhibitor pair with much improved aqueous solubility and Akt2 selectivity. | |
| Akt Inhibitor XIII, Isozyme-Selective, Akti2-1/2 |
Akt
|
Yes
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A water soluble analog of Akt Inhibitor VIII, Isozyme-Selective, Akti-1/2 (Cat. No. 124018) that acts as a non-ATP competitive and an allosteric inhibitor of Akt1/2. | |
| PDK1/Akt/Flt Dual Pathway Inhibitor |
Akt, Flt, PDK1
|
Yes
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A cell-permeable compound that selectively induces apoptosis in AML (Acute Myelogenous Leukemia) with little effect on normal CD34+AML progenitor cells. |
