MK-2206 dihydrochloride 是具有口服活性的，高效选择性的变构Akt抑制剂，对 Akt1、Akt2 和 Akt3 的IC50分别为 8、12 和 65 nM。它具有抗癌活性。

MK-2206 is a highly specific inhibitor of Akt1/2/3 (IC50: 8/12/65 nM in cell-free assays) and no effect on the activities of 250 other protein kinases.

MK-2206 by itself causes growth inhibition of the eight cell lines with an IC50 that ranges between 3.4 and 28.6 μmol/L. MK-2206 alone more potently inhibited the cell growth of Ras wild-type (WT) cell lines (A431, HCC827, and NCI-H292; IC50s of 5.5, 4.3, and 5.2 μmol/L, respectively) as compared with Ras-mutant cell lines (NCI-H358, NCI-H23, NCI-H1299, and Calu-6; IC50s of 13.5, 14.1, 27.0, and 28.6 μmol/L, respectively), with the exception of NCI-H460, which has a PIK3CA E545K mutation (IC50, 3.4 μmol/L) [2]. MK-2206 inhibited the four NPC cell line growths and reduced the sizes of the colonies in a dose-dependent manner. At 72 and 96 hours, the half maximal inhibitory concentration (IC50) values of MK-2206 in CNE-1, CNE-2, and HONE-1 cell lines were 3-5 μM, whereas, in SUNE-1, IC50 was less than 1 μM, and MK-2206 induced cell cycle arrest at the G1 phase [3].

MK-2206 (120 mg/kg) was orally administered 2 hours after erlotinib (50 mg/kg), and tumors were isolated 14 hours after erlotinib administration. MK-2206 alone moderately inhibited phospho-Akt (53.1 ± 6.2%) and only slightly inhibited phospho-Erk (27.7 ± 5.9%). Erlotinib alone only moderately inhibited phospho-Erk, whereas it only slightly, if at all, inhibited phosphor-Akt in the tumor. Cotreatment potentiated the inhibition of phospho-Akt (79.9 ± 3.1%) and phosphor-Erk (53.5 ± 5.8%) [2]. Compared with the control group (30% Captisol diluent), both MK-2206 doses (480 mg/kg once a week and 240 mg/kg three times a week) can inhibit the growth of human CNE-2 xenografts in nude mice. In the two MK-2206 groups, the tumor weights were much lighter than the control group. Temporal body weight reduction was observed after receiving the MK-2206 treatment [3].

Cells were seeded at a density of 2 to 3 × 103 per well in 96-well plates. Twenty-four hours after plating, varying concentrations of the drug, either as a single agent or in combination, were added to the wells. Cell proliferation was determined by using the CellTiter-Glo assay at 72 or 96 hours after dosing. The nature of the drug interaction was evaluated by using the combination index (CI) according to the method of Chou and Talalay. A commercial software package was obtained from Calcusyn. In combination with docetaxel, we tested three treatment sequences: (a) MK-2206 followed by docetaxel—cells were exposed to MK-2206 for 24 hours, and then after washout of MK-2206, cells were treated with docetaxel for an additional 72 hours; (b) docetaxel followed by MK-2206—cells were exposed to docetaxel for 24 hours, and then after washout of docetaxel, cells were treated with MK-2206 for an additional 72 hours; and (c) concurrent treatment—cells were exposed to both MK-2206 and docetaxel for 72 hours [2].

When the mean tumor size reached 0.13 cm3 for the SK-OV-3 or 0.2 cm3 for the NCI-H292, HCC70, PC-3, and NCI-H460 models, the mice were randomized into control and treatment groups with approximately equivalent ranges of tumor volume between groups (n = 5 animals per group). The following vehicles were used to dose the compounds: 30% Captisol (Cydex) for MK-2206; 0.5% methylcellulose + 0.1% Tween 80 for erlotinib; distilled water for lapatinib; 0.73% ethanol in saline for docetaxel; and saline for carboplatin and gemcitabine. The control group received vehicle only. Tumor volume was measured with calipers twice a week. Animal body weight and physical signs were monitored during the experiments. Tumor volume was calculated, taking length to be the longest diameter across the tumor and width to be the perpendicular diameter, by using the following formula: (length × width)2 × 0.5. Relative tumor volume was assessed by dividing the tumor volume on different observation days with the starting tumor volume. Statistical significance was evaluated by using the two-way repeated ANOVA test followed by Dunnett's test or an unpaired t-test [2].

1032350-13-2

C25H23Cl2N5O

480.39

MK-2206 2HCl

DMSO:12 mg/mL (25 mM)
Ethanol:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years