871361-88-5

Akt activation requires binding of its pleckstrin homology domain (PHD) to membrane-associated phosphatidylinositol-3,4,5-trisphosphate (PIP₃) or phosphatidylinositol-3,4-bisphosphate (PIP₂). Increased Akt activity, e.g., through a gain-of-function mutation in the PHD of Akt1, is pivotal to many types of cancer. Activated Akt may be regulated by various events, including ubiquitination-mediated deactivation. SC-66 is an allosteric inhibitor of Akt that facilitates both ubiquitination and deactivation of Akt. At 4 μg/ml, SC-66 inhibits Akt activity in HEK293T cells and in HEK293 cells stably expressing Akt with the gain-of-function pleckstrin homology domain mutation, promoting cell death. In nude mice inoculated with HEK293T cells, SC-66 (15 mg/kg) suppresses tumor growth.

SC 66 is an analog of curcumin that can inhibit the activity of ATP-binding cassette transporters in cancer multidrug resistance.

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[1] HAKRYUL JO. Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108 16: 6486-6491. DOI: 10.1073/pnas.1019062108