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United States (Change Country)MK-2206 2HCl Chemical Structure
MK-2206 dihydrochloride is a highly selective, potent non-ATP competitive allosteric Akt inhibitor with IC50 of 5.3 nM,12 nM, 65 nM for Akt1, Akt2 and Akt3 respectively. MK-2206 dihydrochloride possesses extensively preclinical antitumor activity. In vitro, MK-2206 dihydrochloride synergistically inhibited cell proliferation of human cancer cell lines in combination with molecular targeted agents such as erlotinib or lapatinib. Complementary prevention of erlotinib-insensitive Akt phosphorylation by MK-2206 dihydrochloride was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. 1 hr treatment of 1 μM MK-2206 abolished Akt phosphorylation in U87MG cells. MK-2206 dihydrochloride treatment abolished IR-induced Akt phosphorylation. Moreover, treatment with MK-2206 also increased the radiosensitivity of U87MG cells. [1] MK-2206 dihydrochloride also revealed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 inhibited the Akt phosphorylation that is induced by carboplatin and gemcitabine. [1]
In vivo, MK-2206 dihydrochloride in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. MK-2206 dihydrochloride is generally well tolerated at doses up to 60 mg QOD with plasma concentrations that portend activity in preclinical models. PK/PD results suggest a substantial and maintained target inhibition should at 60 mg. [2] The phase II clinical trials of MK-2206 dihydrochloride against the treatment of endometrial cancer are recruiting participant Dana-Farber Cancer Institute.
[1] Mol Cancer Ther. 2010 Jul;9(7):1956-67.
[2] Meeting: 2009 ASCO Annual Meeting 2009;
| Molecular Weight (WM): | 480.39 |
|---|---|
| Formula: | C25H21N5O.2HCl |
| Solubility(R.T.:25°C): | DMSO 14mg/mL |
| Water 1mg/mL | |
| Ethanol <1mg/mL |
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;Biochim Biophys Acta, 2012, 1823(5), 987-96 MK-2206 2HCl purchased from Selleck
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Data from [J Cell Biochem 2010;112, 924–932] MK-2206 2HCl purchased from Selleck
Data from [Radiat Oncol 2009;4, 43] MK-2206 2HCl purchased from Selleck
Data from [J Cell Biochem 2010;112, 924–932] MK-2206 2HCl purchased from Selleck
Data from [Sci Signal 2011;4, rs9] MK-2206 2HCl purchased from Selleck
;Dr. Zhang of Tianjin Medical University MK-2206 2HCl purchased from Selleck
Data from [J Cell Biochem 2010;112, 924–932] MK-2206 2HCl purchased from Selleck
Qingsong Liu, Ph.DProf. Nathanael Gray Lab Dana-Farber Cancer Institute Biological Chemistry and Molecular Pharmacology Harvard Medical School
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