Melanoma Molecular Maps Projects



Title: List of AKT inhibitors
Legend: Akt (protein kinase B, PKB), a serine/threonine kinase, is critical enzyme in several signal transduction pathways involved in cell proliferation, apoptosis and angiogenesis. Activation of Akt involves growth factor binding to a receptor tyrosine kinase and activation of PI3K, which phosphorylates the membrane bound PIP2 to generate PIP3. The binding of PIP3 to the pleckstrin homology (PH) domain anchors Akt to the plasma membrane and allows its phosphorylation and activation by 3-phosphoinositide dependent kinase-1 (PDK1). High activity of Akt has been detected in many types of human tumors (including melanoma), hence it stands out as a valid molecular target in anticancer targeted therapy. Akt inhibitors have been developed such as A-443654, AKT-in (Akt inhibitor VI), Anti-Akt scFv (anti-Akt single chain antibody), API-2 (Triciribine, Akt inhibitor V), API-59CJ-OMe (Akt inhibitor IX), Canthine alkaloid analogs, Doxazosin derivatives, GSK690693, NL-71-101, PBI-05204, Perifosine, PIA5, PX-316, SH-6 (Akt inhibitor III). Most of them act by inhibiting the PH domain and thus hindering the membrane translocation, as occurs for phosphatidylinositol analogs (they compete with PIP2 [thus preventing PIP3 generation] and with PIP3 [thus inhibiting its binding to Akt]) and the TCL1 derived peptide Akt-in. REFERENCES: [1] Li Q, Expert Opinion Therapeutic Patents 2007, 17:1077-130. [2] Lopiccolo J et al, Anticancer Drugs 2007, 18:861-74. [3] Lindsley CW et al, Curr Top Med Chem 2007, 7:1349-63. [4] Robertson GP, Cancer Metastasis Rev 2005, 24:273-85.
Author: The MMMP Team (updated: Jan 2008)

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