MK-2206 dihydrochloride
(Synonyms: MK-2206,MK2206,MK 2206) 目录号 : GC16304
MK-2206双盐酸盐是一种口服活性的变构Akt抑制剂，用于治疗实体肿瘤。
Cas No.:1032350-13-2
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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| Cell experiment [1]: | |
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Cell lines |
NCI-H292 NSCLC cells |
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Preparation Method |
Cells were treated with MK-2206 (0, 0.3, 1, and 3 μmol/L) in the presence or absence of erlotinib (0, 0.6, 2.5, 10, and 20 μmol/L) for 48 h. Apoptosis was evaluated by measuring the caspase-3/7 activity. |
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Reaction Conditions |
MK-2206 (0, 0.3, 1, and 3 μmol/L), 48h |
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Applications |
Caspase activation became apparent at 2.5 μmol/L erlotinib and 3 μmol/L MK-2206 or higher. |
| Animal experiment [2]: | |
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Animal models |
female nu/nu mice |
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Preparation Method |
1 × 107 ZR75-1 breast cancer cells were inoculated in the mammary fat pads of female nu/nu mice. Mice were subcutaneously implanted with 17β-estradiol pellets. Mice bearing ZR75-1 xenografts were randomized into 3 groups (vehicle, MK-2206 240 mg/kg, or 480 mg/kg, n = 5–6). Tumor measurements were followed to assess antitumor efficacy, and RPPA was utilized to assess the effect on cell signaling as described above. |
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Dosage form |
240 mg/kg, or 480 mg/kg, p.o. |
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Applications |
MK-2206 (240 mg/kg, or 480 mg/kg) inhibits tumor growth in ZR75-1 xenografts. |
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References: [1]. Hirai H, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010 Jul;9(7):1956-67. [2]. Xing Y, et al. Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation. Breast Cancer Res. 2019 Jul 5;21(1):78. |
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MK-2206 dihydrochloride is an orally active allosteric Akt inhibitor used in treatment of solid tumors.[1]
IIn vitro experiment it shown that MK-2206 is equally potent toward purified recombinant human Akt1 and Akt2 enzyme with IC50 of 5 nmol/L and 12 nmol/L, respectively; and approximately 5-fold less potent against human Akt3 (IC50, 65 nmol/L). MK-2206 potently inhibited the cell growth of Ras wild-type (WT) cell lines (A431, HCC827, and NCI-H292 with IC50s of 5.5, 4.3, and 5.2 μmol/L, respectively. The combination of 2.5 μmol/L erlotinib and 3 μmol/L MK-2206 or higher obviously activated the caspase.[1] In vitro, Akt inhibitor (MK 2206 dihydrochloride, 2.5 nM) reduces the effects of anti-microRNA-320a on the apoptosis of MDA-MB-231 cells.[2] In vitro, treatment with 0.1 and 1 μM for 48 h MK-2206 reduced the expression p-Akt in all pancreatic cancer cell lines suggesting that MK-2206 inhibited Akt phosphorylation in pancreatic cancer cells.[3] In vitro the colony formation assay confirmed that 1 μM of MK-2206 significantly inhibited the proliferation of SGC-7901 cells.[4]
In vivo test displayed it that treatment with 120 mg/kg MK-2206 orally 2 hours after erlotinib (50 mg/kg), and tumors were isolated 14 hours after erlotinib administration to verify the inhibition of phospho-Akt for the PI3K pathway and phospho-Erk for the Ras/Erk pathway. In vivo efficacy studies it demonstrated that the antitumor efficacy of MK-2206 with once a week at 360 mg/kg intermittently dosing was quite similar to the efficacy of three times a week at 120 mg/kg dosing when MK-2206 was combined with erlotinib.[1].
References:
[1]. Hirai H, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010 Jul;9(7):1956-67.
[2]. Guan J, et al. MicroRNA 320a suppresses tumor cell growth and invasion of human breast cancer by targeting insulin like growth factor 1 receptor. Oncol Rep. 2018 Aug;40(2):849-858.
[3]. Wang Z, et al. Akt inhibitor MK-2206 reduces pancreatic cancer cell viability and increases the efficacy of gemcitabine. Oncol Lett. 2020 Mar;19(3):1999-2004.
[4]. Jin P, et al. MK-2206 co-treatment with 5-fluorouracil or doxorubicin enhances chemosensitivity and apoptosis in gastric cancer by attenuation of Akt phosphorylation. Onco Targets Ther. 2016 Jul 19;9:4387-96.
MK-2206双盐酸盐是一种口服活性的变构Akt抑制剂，用于治疗实体肿瘤。
在体外实验中，MK-2206对纯化的重组人Akt1和Akt2酶表现出相同的强效作用，IC50分别为5 nmol/L和12 nmol/L；而对人类Akt3则大约弱了5倍（IC50为65 nmol/L）。MK-2206能够有效抑制Ras野生型（WT）细胞系（A431、HCC827和NCI-H292），其IC50分别为5.5、4.3和5.2 μmol/L。2.5 μmol/L厄洛替尼与3 μmol/L或更高剂量的MK-2206联合使用明显激活了半胱氨酸蛋白酶。[1] 在体外实验中，Akt抑制剂（MK 2206二盐酸盐，2.5 nM）减少了MDA-MB-231细胞抗microRNA-320a诱导的凋亡效应。[2] 在体外实验中，48小时以0.1μM和1μM浓度处理MK-2206可降低所有胰腺癌细胞系p-Akt表达水平，这表明MK-2206可以抑制胰腺癌细胞内部的Akt磷酸化过程。[3] 在体外结节形成试验中证实，在SGC-7901细胞中使用1μM的MK-2206可以显著抑制其增殖。[4]
实验结果显示，口服120毫克/千克的MK-2206治疗剂量，在埃洛替尼（50毫克/千克）给药后2小时内进行，并在埃洛替尼给药后14小时分离肿瘤以验证PI3K通路的磷酸化Akt和Ras / Erk通路的磷酸化Erk抑制。体内有效性研究表明，当MK-2206与埃洛替尼联合使用时，每周一次360毫克/千克间歇性给药的抗肿瘤效果与每周三次120毫克/千克给药相似。[1]
| Cas No. | 1032350-13-2 | SDF | |
| 别名 | MK-2206,MK2206,MK 2206 | ||
| 化学名 | 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride | ||
| Canonical SMILES | C1CC(C1)(C2=CC=C(C=C2)C3=C(C=C4C(=N3)C=CN5C4=NNC5=O)C6=CC=CC=C6)N.Cl.Cl | ||
| 分子式 | C25H21N5O.2HCl | 分子量 | 480.39 |
| 溶解度 | ≥ 12.01mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0816 mL | 10.4082 mL | 20.8164 mL |
| 5 mM | 0.4163 mL | 2.0816 mL | 4.1633 mL |
| 10 mM | 0.2082 mL | 1.0408 mL | 2.0816 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Glypican 1 promotes proliferation and migration in esophagogastric adenocarcinoma via activating AKT/GSK/β-catenin pathway
Background: Glypican 1 (GPC1) is a heparan sulphate proteoglycan cell membrane protein. It is implicated in driving cancers of the breast, brain, pancreas, and prostate; however, its role in esophagogastric cancer (EGAC) remains unexplored. The aim of the study was to investigate and elucidate the molecular mechanistic of GPC1 in human EGAC. Methods: Thirty tissue and 120 microarray sections of EGAC were evaluated with Anti-GPC1 immunohistochemistry. Loss and gain of GPC1 function were performed using lentivirus transfection in EGAC cell lines. Mechanistically, AKT/GSK/β-catenin pathway was evaluated using AKT inhibitor MK-2206 and Wnt/β-catenin stimulant LiCl. Results: GPC1 overexpression was found in 102 cases (68%). Overexpression of GPC1 correlated with lymph node metastasis, poor differentiation and decreased overall survival. Lentivirus mediated GPC1 knockdown resulted in decreased cell proliferation, migration, invasion, and colony formation. Knockdown caused G0/G1 cell cycle arrest, increased apoptosis, and reduced epithelial mesenchymal transition (EMT). GPC1 mediated its effects by activation of AKT/GSK/β-catenin pathway. Conclusions: This is the first descriptive study to decipher the role of GPC1 in EGAC. Our results suggest that GPC1 regulates cell proliferation and growth and may serve as an attractive oncotarget in EGAC.
Context-dependent antagonism between Akt inhibitors and topoisomerase poisons
Signaling through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which is aberrantly activated in >50% of carcinomas, inhibits apoptosis and contributes to drug resistance. Accordingly, several Akt inhibitors are currently undergoing preclinical or early clinical testing. To examine the effect of Akt inhibition on the activity of multiple widely used classes of antineoplastic agents, human cancer cell lines were treated with the Akt inhibitor A-443654 [(2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan-2-amine; ATP-competitive] or MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride; allosteric inhibitor) or with small interfering RNA (siRNA) targeting phosphoinositide-dependent kinase 1 (PDK1) along with cisplatin, melphalan, camptothecin, or etoposide and assayed for colony formation. Surprisingly different results were observed when Akt inhibitors were combined with different drugs. Synergistic effects were observed in multiple cell lines independent of PI3K pathway status when A-443654 or MK-2206 was combined with the DNA cross-linking agents cisplatin or melphalan. In contrast, effects of the Akt inhibitors in combination with camptothecin or etoposide were more complicated. In HCT116 and DLD1 cells, which harbor activating PI3KCA mutations, A-443654 over a broad concentration range enhanced the effects of camptothecin or etoposide. In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (>80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents. These results indicate that the effects of combining inhibitors of the PI3K/Akt pathway with certain classes of chemotherapeutic agents might be more complicated than previously recognized.
Phosphacan acts as a repulsive cue in murine and rat cerebellar granule cells in a TAG-1/GD3 rafts-dependent manner
Phosphacan, a chondroitin sulfate proteoglycan, is a repulsive cue of cerebellar granule cells. This study aims to explore the molecular mechanism. The glycosylphosphatidylinositol-anchored neural adhesion molecule TAG-1 is a binding partner of phosphacan, suggesting that the repulsive effect of phosphacan is possibly because of its interaction with TAG-1. The repulsive effect was greatly reduced on primary cerebellar granule cells of TAG-1-deficient mice. Surface plasmon resonance analysis confirmed the direct interaction of TAG-1 with chondroitin sulfate C. On postnatal days 1, 4, 7, 11, 15, and 20 and in adulthood, phosphacan was present in the molecular layer and internal granular layer, but not in the external granular layer. In contrast, transient TAG-1 expression was observed exclusively within the premigratory zone of the external granular layer on postnatal days 1, 4, 7, and 11. Boyden chamber cell migration assay demonstrated that phosphacan exerted its repulsive effect on the spontaneous and brain-derived neurotrophic factor (BDNF)-induced migration of cerebellar granule cells. The BDNF-induced migration was inhibited by MK-2206, an Akt inhibitor. The pre-treatment with a raft-disrupting agent, methyl-β-cyclodextrin, also inhibited the BDNF-induced migration, suggesting that lipid rafts are involved in the migration of cerebellar granule cells. In primary cerebellar granule cells obtained on postnatal day 7 and cultured for 7 days, the ganglioside GD3 and TAG-1 preferentially localized in the cell body, whereas the ganglioside GD1b and NB-3 localized in not only the cell body but also neurites. Pre-treatment with the anti-GD3 antibody R24, but not the anti-GD1b antibody GGR12, inhibited the spontaneous and BDNF-induced migration, and attenuated BDNF-induced Akt activation. These findings suggest that phosphacan is responsible for the repulsion of TAG-1-expressing cerebellar granule cells via GD3 rafts to attenuate BDNF-induced migration signaling.
Thiocoraline mediates drug resistance in MCF-7 cells via PI3K/Akt/BCRP signaling pathway
Thiocoraline, a depsipeptide bisintercalator with potent antitumor activity, was first isolated from marine actinomycete Micromonospora marina. It possesses an intense toxicity to MCF-7 cells at nanomolar concentrations in a dose-dependent manner evaluated by MTT assay and crystal violet staining. We established a human breast thiocoraline-resistant cancer subline of MCF-7/thiocoraline (MCF-7/T) to investigate the expression variation of breast cancer resistance proteins (BCRP) and its subsequent influence on drug resistance. Colony-forming assay showed that the MCF-7 cells proliferated faster than the MCF-7/T cells in vitro. Western blot analysis demonstrated that thiocoraline increased the phosphorylation of Akt. Additionally, the sensitivity of tumor cells to thiocoraline was reduced with a concurrent rise in phosphorylation level of Akt and of BCRP expression.These studies indicated that thiocoraline probably mediated the drug resistance via PI3K/Akt/BCRP signaling pathway. MK-2206 dihydrochloride, a selective phosphorylation inhibitor of Akt, significantly decreased MCF-7 cell viability under exposure to thiocoraline compared to the control. However, it was not obviously able to decrease MCF-7/T cell viability when cells were exposed to thiocoraline.
MicroRNA?320a suppresses tumor cell growth and invasion of human breast cancer by targeting insulin?like growth factor 1 receptor
The present study was performed to investigate the biological functions of microRNA?320a in human breast cancer and the underlying mechanisms. MicroRNA?320a expression was downregulated in human breast cancer, compared with the normal control. Overexpression of microRNA?320a induced apoptosis, and inhibited cell viability and invasion in MDA?MB?231cells while downregulation of microRNA?320a reduced apoptosis, and increased cell viability and invasion in MDA?MB?231 cells. Then, overexpression of microRNA?320a suppressed insulin?like growth factor 1 receptor (IGF?1R), p?AKt and cyclin D1 protein expression in MDA?MB?231cells. In addition, the downregulation of microRNA?320a induced IGF?1R, p?Akt and cyclin D1 protein expression in MDA?MB?231cells. Furthermore, the IGF?1R inhibitor increased the effects of microRNA?320a on the apoptosis of MDA?MB?231 cells. The p?Akt inhibitor (MK 2206 dihydrochloride, 2.5 nM) increased the effects of microRNA?320a on the apoptosis of MDA?MB?231 cells. These results revealed that microRNA?320a suppresses tumor cell growth and invasion of human breast cancer by targeting IGF?1R.