MK-2206 2HCl

製品コードS1078 バッチS107811

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C25H21N5O.2HCl
分子量 480.39 CAS No. 1032350-13-2
Solubility (25°C)* 体外 DMSO 96 mg/mL (199.83 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 MK-2206 2HCl は高い選択性をもつ Akt1/2/3 阻害剤であり、cell-free assay における IC50 はそれぞれ 8 nM/ 12 nM/ 65 nM です。一方で、他の250種におよぶキナーゼ (kinases) に対しては活性が検出されていません。MK-2206 2HCl はがん細胞におけるオートファジー (autophagy) やアポトーシス (apoptosis) に関与します。臨床第2相試験中
in vitro MK-2206 is an allosteric inhibitor and is activated by the pleckstrin homology domain. MK-2206 inhibits auto-phosphorylation of both Akt T308 and S473. MK-2206 also prevents Akt-mediated phosphorylation of downstream signaling molecules, including TSC2, PRAS40 and ribosomal S6 proteins. [1] MK-2206 inhibits Ras wild-type (WT) cell lines (A431, HCC827, and NCI-H292) more potently when compared to Ras-mutant cell lines (NCI-H358, NCI-H23, NCI-H1299, and Calu-6). MK-2206 also shows synergistic responses in combination with cytotoxic agents such as erlotinib or lapatinib in lung NCI-H460 or ovarian A2780 tumor cells. [2] MK-2206 or siRNA-mediated Akt inhibition strongly activates autophagy in human glioma cells. However, eukaryotic elongation factor-2 (eEF-2) silencing suppresses MK-2206-induced-autophagy, with a promotion of apoptotic cell death. [3]
in vivo MK-2206 shows 60% TGI and inhibits more than 70 % of phospho-Akt1/2 (T308 and S473) in A2780 ovarian cancer xenografts at a dose of 240 mg/kg. [1] MK-2206 exhibits significant antitumor activity in NCI-H292 xenograft in combination with erlotinib or lapatinib. [2]
特徴 The first allosteric small molecule inhibitor of Akt to enter clinical development.

プロトコル(参考用のみ)

キナーゼアッセイ Akt kinases assay
Akt kinases are assayed by a GSK-derived biotinylated peptide substrate. The extent of peptide phosphorylation is determined by Homogeneous Time Resolved Fluorescence (HTRF) using a lanthanide chelate (Lance)-coupled monoclonal antibody specific for the phosphopeptide in combination with a streptavidin-linked allophycocyanin (SA-APC) fluorophore which will bind to the biotin moiety on the peptide. When the Lance and APC are in proximity, a non-radiative energy transfer takes place from the Lance to the APC, followed by emission of light from APC at 655 nm. Working Solution: 100X protease inhibitor cocktail (PIC): 1mg/mL benzamidine, 0.5 mg/mL pepstatin, 0.5 mg/mL leupeptin, 0.5 mg/mL aprotinin; 10X assay buffer: 500 mM HEPES, pH7.5, 1% PEG, 16.6 mM EDTA, 1 mM EGTA, 1% BSA, 20 mM 9-glycerol phosphate; Quench buffer 50 mM HEPES pH 7.3, 16.6 mM EDTA, 0.1% BSA, 0.1% Triton X-100, 0.17 nM labeled monoclonal antibody, 0.0067 mg/mL SA-APC; ATP/MgCl2 working solution: 1X Assay buffer, 1 mM DTT, 1X PIC, 5% glycerol, active Akt; Peptide working solution: 1X Assay buffer, 1 mM DTT, 1X PIC, 5% glycerol, 2 TM GSK biotinylated peptide. The reaction is assembled by adding 16 µL of ATP/MgCl2 working solution to the appropriate wells. MK-2206 or vehicle (1.0 µL) is added followed by 10 µL of peptide working solution. The reaction is started by adding 13 μL of the enzyme working solution and mixing. The reaction is allowed to proceed for 50 min and then stopped by the addition of 60 µL HTRF quench buffer. The stopped reactions are incubated at room temperature for at least 30 min and then read in the instrument.
細胞アッセイ 細胞株 A431, HCC827, NCI-H292, NCI-H358, NCI-H23, NCI-H1299, Calu-6 and NCI-H460 cells
濃度 0, 0.3, 1 and 3 μM
反応時間 72 or 96 hours
実験の流れ

MK-2206 is dissolved in DMSO as a stock solution and diluted by culture media before use. Cells are seeded at a density of 2-3 × 103 in 96-well plates and incubated for 24 hours. Then MK-2206 (0, 0.3, 1 and 3 μM) is added to the cells. Cell proliferation is determined after 72 or 96 hours.
動物実験 動物モデル SK-OV-3, NCI-H292, HCC70, PC-3, and NCI-H460 models in male CD1-nude mice
投薬量 120 mg/kg
投与方法 Orally administered

カスタマーフィードバック

Data from [Data independently produced by Nat Commun, 2015, 6:6943]

Data from [Data independently produced by Leukemia, 2015, 29(1), 169-76]

Data from [Data independently produced by J Exp Med, 2014, 211(9), 1741-58]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation [ Nat Commun, 2024, 15(1):2089] PubMed: 38453961
AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis [ Nat Commun, 2024, 15(1):686] PubMed: 38263319
PD-L1-expressing tumor-associated macrophages are immunostimulatory and associate with good clinical outcome in human breast cancer [ Cell Rep Med, 2024, 5(2):101420] PubMed: 38382468
UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT [ Int J Biol Sci, 2024, 20(4):1389-1409] PubMed: 38385072
CUL4B mutations impair human cortical neurogenesis through PP2A-dependent inhibition of AKT and ERK [ Cell Death Dis, 2024, 15(2):121] PubMed: 38331954
Tumor suppressor let-7 acts as a key regulator for pluripotency gene expression in Muse cells [ Cell Mol Life Sci, 2024, 81(1):54] PubMed: 38261036
Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology [ EMBO Rep, 2024, none] PubMed: 38413732
Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models [ Gastric Cancer, 2024, 10.1007/s10120-024-01468-8] PubMed: 38261067
PKCiota Inhibits the Ferroptosis of Esophageal Cancer Cells via Suppressing USP14-Mediated Autophagic Degradation of GPX4 [ Antioxidants (Basel), 2024, 13(1)114] PubMed: 38247539
Isoxanthohumol reduces neointimal hyperplasia through the apelin/AKT pathway [ Biochim Biophys Acta Mol Basis Dis, 2024, 1870(4):167099] PubMed: 38428686

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人間や獣医の診断であるか治療的な使用のためにでない。

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