MK-2206 is a highly selective non-ATP competitive allosteric Akt inhibitor that is equally potent towards purified recombinant human Akt1 and Akt2 and approximately five fold less potent against human Akt3 (IC50= 8, 12, and 65 nM, respectively) in enzyme assays. MK-2206 (0-10 μM) decreases both Thr 308 and Ser 473 p-Akt levels in T-cell acute lymphoblastic leukemia (T-ALL) cell lines, MOLT-4, CEM-R and CEM-S , in a concentration-dependent manner, resulting in dephosphorylation of GSK3-α/β (Ser 21/9 ) and FoxO3A (Thr-32). MK-2206 also decreases the levels of Ser 2481 p-mTOR. The IC50 values of MK-2206 are 1.7, 3.3 and 5.1 μM for T-ALL cell lines, MOLT-4, CEM-R and CEM-S, respectively. MK-2206 treatment (1-3 μM) results in an increase in MOLT-4 cells in the G0/G1 phase and in a decrease in cells in S phase in a concentration-dependent manner. The levels of colony-forming unit (CFU)-leukemia formation from three different T-ALL samples are markedly reduced with a mean decrease from 63 to 21%, after treatment with 0.5??.0 μM MK-2206.[1] The median relative IC50 value of MK-2206 for the Pediatric Preclinical Testing Program (PPTP) cell lines is 2.2 μM, with a range from 0.05 μM for the T-cell ALL line COG-LL-317 to greater than 10 μM for the glioblastoma cell line SJ-GBM2. There are four cell lines with IC50 values of MK-2206 < 200 nM: two acute lymphoblastic leukemia (ALL) cell lines (COG-LL-317 and RS4;11), an acute myelocytic leukemia (AML) cell line with an activating KIT mutation (Kasumi-1), and a Ewing sarcoma cell line (CHLA-10).[2] In human glioma LN229 and T98G cells, Akt inhibition by MK-2206 (2.5, 5 or 10 μM) or siRNA-mediated attenuation strongly activates autophagy, whereas silencing of eukaryotic elongation factor-2 (eEF-2) kinase, a protein synthesis regulator, blunts this autophagic response.[3] In HCC70 human breast carcinoma xenograft model, MK-2206 (120 mg/kg) alone shows moderate tumor growth inhibition and the combination of lapatinib (100 mg/kg) and MK-2206 (120 mg/kg) has a significantly greater inhibition of HCC70 tumor growth than either agent alone. Besides, in SK-OV-3 human ovarian cancer xenograft model, lapatinib (100 mg/kg) or MK-2206 (120 mg/kg) alone moderately inhibits SK-OV-3 tumor growth, the combination of lapatinib (100 mg/kg) and MK-2206 (120 mg/kg) yields a significantly greater antitumor effect than either agent alone, and in a dose-dependent manner. In a PC-3 xenograft model (human prostate cancer cell line), docetaxel (5 mg/kg) or MK-2206 (120 mg/kg) alone shows moderate antitumor efficacy and cotreatment with docetaxel followed by MK-2206 exhibits greater tumor growth inhibition than each agent alone. Mice who received docetaxel alone, MK-2206 alone, or both agents lose body weight (4%, 8%, and 9%, respectively) during the treatment period. However, their weight returns to the pretreatment level after the end of treatments.[4] |