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.
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]
| 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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| 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 | ||||||||||
| 计算重置 | ||||||||||
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。
Quality Control & SDS
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- Purity: >98.00%
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