MK-2206, a potent Akt inhibitor

by Selleckchem | Oct 16 2012

Characterization of MK-2206
Akt is identified as a serine-threonine kinase on the basis of its homology to protein kinase A (PKA), protein kinase C (PKC) and the retroviral oncogene, viral Akt. The known three human AKT isozymes (Akt1, Akt2 and Akt3) are highly homologous multi-domain proteins with both overlapping and distinct cellular functions. So far, there are a lot of AKT isozyme-selective allosteric inhibitors that have been reported, and MK-2206 is one member of them. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms, which binds to a site outside the PH domain and binds very weakly to the PH domain of Akt. MK-2206 has the solubility around 96 mg/mL in both dimethyl sulfoxide (DMSO) and water, however it is scarcely soluble in ethanol with solubility of 2 mg/mL. And the approximate price of MK-2206 is $214 per 10 mg and $718 per 50 mg in selleckchem.com, and MK-2206 price may vary according to the proportion purity of the preparation and/or from one MK-2206 supplier to different ones.

IN VITRO ACTIVITIES
Kinase assays show that MK-2206 produces the potent inhibitory activities against Akt1, Akt2 and Akt3 with IC50 of 8 nM, 12 nM and 65 nM, respectively. [1] In vitro, MK-2206 potently inhibits Thr308Akt and Ser473Akt phosphorylation in 3T3-L1 adipocytes with IC50 of 0.11μM and 0.18 μM respectively, and also show the inhibition effect on downstream effects of insulin on GLUT4 (glucose transporter 4) translocation and glucose transport with IC50 of 0.47 μM and 0.14 μM, respectively. [2] In addition, synergy has been observed with combined use of MK-2206 and other targeted therapies. For example, MK-2206 leads to synergistic growth inhibition in combination of with erlotinib in NSCLC cell lines and with lapatinib in breast cancer cell lines. [1] In thyroid cancer cells, MK2206 also completely overcomes the feedback activation of Akt from temsirolimus-induced mTOR suppression and inhibits cancer cell growth. [3] Moreover, MK-2206 also has been found to strongly activate autophagy in human glioma cells. [4]

IN VIVO ACTIVITIES
In vivo xenograft studies utilizing mice bearing the A2780 ovarian cancer cell line, MK-2206 treatment results in roughly 60% tumor growth inhibition and sustained inhibition of all three Akt isoforms. [5] In neuroblastoma xenograft mouse model, MK-2206 in combination with etoposide or rapamycin causes a more significant decrease in tumor growth and increase of murine survival compared with MK-2206 alone. [6] These studies support the potential clinical use of MK-2206 as a partner for conventional drugs. The studies of clinical trails about MK-2206 has been elaborated in the previous article.

REFERENCES
[1] Yan L, et al. AACR Annual Meeting 2009: Abstract Number: DDT01-1.
[2] Tan, et al. Next-generation Akt inhibitors provide greater specificity: effects on glucose metabolism in adipocytes.
[3] Liu R, et al. The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. J Clin Endocrinol Metab. 2011, 96(4), E577-585.
[4] Cheng Y, et al. eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206. Cancer Res, 2011, 71(7), 2654-2663.
[5] Lu W, et al. In vitro and in vivo antitumor activities of MK-2206, a new allosteric Akt inhibitor; AACR Meeting Abstracts; 2009. p. 3714.
[6] Li Z, et al. Combination of an allosteric Akt Inhibitor MK-2206 with etoposide or rapamycin enhances the antitumor growth effect in neuroblastoma. Clin Cancer Res. 2012, 18(13), 3603-3615.

Cat.No.	Product Name	Information
S1078	MK-2206 2HCl	MK-2206 2HCl is a highly selective inhibitor of Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; no inhibitory activities against 250 other protein kinases observed. MK-2206 2HCl induces autophagy and apoptosis in cancer cells. Phase 2.
S1203	T16Ainh-A01	T16Ainh-A01 is a potent and selective inhibitor of calcium-activated chloride channel (CaCC)/transmembrane protein 16A (TMEM16A, ANO1) with IC50 of 1.8 μM.
S1044	Temsirolimus	Temsirolimus is a specific mTOR inhibitor with IC50 of 1.76 μM in a cell-free assay. Temsirolimus induces autophagy and apoptosis.
S1225	Etoposide	Etoposide is a semisynthetic derivative of podophyllotoxin, which inhibits DNA synthesis via topoisomerase II inhibition activity which enhances double-strand and single-strand cleavage of DNA and reversibly inhibits repair by topoisomerase II binding. Etoposide induces autophagy, mitophagy and apoptosis.
S1039	Rapamycin	Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM in HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.