MK-2206 dihydrochloride - CAS 1032350-13-2
Catalog number: B0084-336879
Category: Inhibitor
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Molecular Formula:
C25H23Cl2N5O
Molecular Weight:
480.4
COA:
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Targets:
Akt
Description:
MK-2206 is a highly selective Akt inhibitor with IC50 of 8 nM, 12 nM and 65 nM for Akt1, Akt2 and Akt3, respectively. It is undergoing a phase II clinical trial for the treatment of ovarian, fallopian tube, or primary peritoneal cancer where there are mutations in P13K or AKT or low levels of PTEN.
Ordering Information
Catalog Number Size Price Stock Quantity
B0084-336879 100 mg $198 In stock
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Purity:
>98%
Related CAS:
1032349-77-1; 1032349-93-1
Appearance:
White Solid
Synonyms:
MK-2206. MK 2206. MK2206.
MSDS:
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InChIKey:
HWUHTJIKQZZBRA-UHFFFAOYSA-N
InChI:
InChI=1S/C25H21N5O.2ClH/c26-25(12-4-13-25)18-9-7-17(8-10-18)22-19(16-5-2-1-3-6-16)15-20-21(27-22)11-14-30-23(20)28-29-24(30)31;;/h1-3,5-11,14-15H,4,12-13,26H2,(H,29,31);2*1H
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
Current Developer:
Merck
1.MK-2206 induces apoptosis of AML cells and enhances the cytotoxicity of cytarabine
Jeng-Wei Lu • Yu-Min Lin • Yen-Ling Lai. Med Oncol (2015) 32:206
The phosphoinositide 3-kinase (PI3K)/AKT pathway has been postulated to be an effective therapeutic target in various human cancers. The serine/threonine kinase AKT, a critical signaling node downstream of PI3K, has been coined down to be potentially important target for cancer treatment. MK-2206 [8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f][1,6]naphthyridin- 3(2H)-one dihydrochloride] (Fig. 1a), a small molecule allosteric inhibitor of AKT, has emerged as a potential anticancer agent. MK-2206 inhibits thyroid cancer cells with mutations in PI3K/AKT signaling, disrupts metastasis in an orthotopic model of head and neck squamous cell carcinoma (HNSCC), and induces apoptosis accompanying with eEF-2 kinase-mediated autophagy in glioma cells. Recently, MK-2206 was reported to have cytotoxic activity against T cell acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma, and chronic lymphocytic leukemia (CLL) in cell lines and primary cells. Clinical trial revealed that MK-2206 with maximum-tolerated dose of 60 mg on alternate days (QOD) was well tolerated and showed evidence of AKT signaling blockade in patients with several locally advanced or metastatic solid tumors.
2.Scheduledependent modulation of the pharmacokinetics of MK2206, an oral panAKT inhibitor: perspectives
Nuggehally R. Srinivas. Cancer Chemother Pharmacol (2015) 76:1315–1316
In summary, the excellent work of Doi et al. have provided excellent comparative pharmacokinetic data of QOD versus QW dosing schedules of MK-2206. Therefore, it appeared that both these schedules may serve well for the further development of MK-2206. However, a rational decision for selecting one over the other schedule of MK-2206 would be dependent on the co-administered drug in the combination therapy keeping in mind two important pharmacokinetic variables high transient peak concentration from the QW dose versus higher trough levels from the QOD dose of MK-2206 from a drug–drug interaction potential with the co-administered drug.
3.The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells
Ying-Hsi Lin & Bert Yu-Hung Chen & Wei-Ting Lai . Naunyn-Schmiedeberg's Arch Pharmacol (2015) 388:19–31
It has been found that overexpression of constitutively active Akt partially prevents mitochondrial damage, while inhibition of Akt induces mitochondrial impairment associated with opening of the permeability transition pore (Caro and Cederbaum 2006). Therefore, MK-2206 may induce the loss of mitochondrial integrity and the overproduction of reactive oxygen species (ROS) to increase apoptosis. Previous studies also showed that inhibition of mTOR by rapamycin disrupts DNA double-strand break (DSB) repair by impairing the recruitment of proteins essential for homologous recombination (Chen et al. 2011). One such protein is BRCA1, which recognizes DNA damage lesions, translocates to DNA damage sites, forms nuclear foci at DNA lesions, functions in the DNA damage response, and is critical for maintaining genomic integrity and chromosomal stability (Scully et al. 1997; Paull et al. 2000). The Akt inhibitor MK-2206 may be able to disrupt phosphorylation and activation of mTOR and sensitize ovarian cancer cells to DNA damaging agents, such as cisplatin, by compromising DNA repair.
4.Preclinical evaluation of the AKT inhibitor MK-2206 in nasopharyngeal carcinoma cell lines
Brigette B. Y. Ma & Vivian W. Y. Lui & Connie W. C. Hui. Invest New Drugs (2013) 31:567–575
MK-2206 had a similar inhibitory effect on mTOR signaling as on AKT, but the effect was more modest and after more prolonged drug exposure. The effect of MK-2206 on the expression of total and phosphorylated p-4EBP1 and p-70S6K(Thr 398)—the 2 main downstream effectors of mTOR—varied between different NPC cell lines. MK- 2206 had a modest effect on the level of total and phosphorylated p70S6K in CNE-2 cells, while the effect in C666-1 and HONE-1-EBV cells was negligible. MK-2206 had a more significant effect on reducing the level of total and phosphorylated 4EBP1 in CNE-2 and C666-1 cell lines than in HONE-1-EBV cell lines.
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CAS 1032350-13-2 MK-2206 dihydrochloride

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