Aberrant activation of the serine/threonine kinase Akt, a central node of the PI3K pathway, has been found in a significant proportion of human solid tumors, making Akt an attractive target for therapeutic intervention. MK-2206 is a potent inhibitor of Akt isozymes 1, 2, and 3 with in vitro IC50 values of 8, 12, and 65 nM, respectively. The compound is an allosteric inhibitor of Akt, requiring the presence of the Pleckstrin homology domain for activity. As a consequence, MK-2206 is highly selective against Akt, exhibiting no inhibitory activities against over 250 protein kinases when tested at 1\#956;M. In several cancer cell lines, MK-2206 potently inhibited Akt1 kinase activity (IC50 \#8776; 20 nM), and blocked Akt2 and Akt3 activities 2- to 6-fold less potently. MK-2206 potently inhibited phosphorylation of T308 and S473 of Akt in these cell lines and prevented Akt-mediated phosphorylation of down-stream signaling molecules, including TSC2, PRAS40 and ribosomal S6 proteins. MK-2206 exhibited potent anti-proliferative activity against a number of cancer cell lines harboring one or more of the following genetic defects: 1) constitutive activation of receptor tyrosine kinases such as HER2; 2) PTEN mutation, 3) PI3KCA mutation, and 4) Akt2 amplification. In nude mice bearing A2780 ovarian cancer xenografts, a single oral dose of MK-2206 at 240 mg/kg caused sustained inhibition (>70 %) of phospho-Akt1/2 (T308 and S473) in the tumors. In the same tumor model, MK-2206 inhibited tumor growth by \#8776; 60% when administrated orally at 240 mg/kg per day three times a week. These preclinical results support further clinical development of MK-2206.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3714.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO