MK-2206 dihydrochloride|1032350-13-2|安捷凯

Background

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].

参考文献:
[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]

Protocol

Cell experiment [1]:

Cell lines

NCI-H292 NSCLC cells

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.

Reaction Conditions

MK-2206 (0, 0.3, 1, and 3 μmol/L), 48h

Applications

Caspase activation became apparent at 2.5 μmol/L erlotinib and 3 μmol/L MK-2206 or higher.

Animal experiment [2]:

Animal models

female nu/nu mice

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.

Dosage form

240?mg/kg, or 480?mg/kg, p.o.

Applications

MK-2206 (240?mg/kg, or 480?mg/kg) inhibits tumor growth in ZR75-1 xenografts.

参考文献:

[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

MK-2206 dihydrochloride详情

Background

Protocol

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