A-443654

Akt inhibitor,potent and selective CAS# 552325-16-3

A-443654

Catalog No. BCC1321----Order now to get a substantial discount!

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Chemical structure

A-443654

3D structure

Chemical Properties of A-443654

Cas No. 552325-16-3 SDF Download SDF
PubChem ID 10172943 Appearance Powder
Formula C24H23N5O M.Wt 397.48
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 100 mg/mL (251.59 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan-2-amine
SMILES CC1=C2C=C(C=CC2=NN1)C3=CC(=CN=C3)OCC(CC4=CNC5=CC=CC=C54)N
Standard InChIKey YWTBGJGMTBHQTM-IBGZPJMESA-N
Standard InChI InChI=1S/C24H23N5O/c1-15-22-10-16(6-7-24(22)29-28-15)17-9-20(13-26-11-17)30-14-19(25)8-18-12-27-23-5-3-2-4-21(18)23/h2-7,9-13,19,27H,8,14,25H2,1H3,(H,28,29)/t19-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of A-443654

DescriptionA-443654 is a potent and selective inhibitor of Akt1 with Ki value of 160 pM.
TargetsAkt1    
IC50160 pM (Ki)     

Protocol

Cell Assay [1]
The cells on 96-well plates are gently washed with 200 μL of PBS. Alamar Blue reagent is diluted 1:10 in normal growth media. The diluted Alamar Blue reagent (100 μL) is added to each well on the 96-well plates and incubated until the reaction is complete as per manufacturer's instructions. Analysis is done using an fmaxFluorescence Microplate Reader, set at the excitation wavelength of 544 nm and emission wavelength of 595 nm. Data are analyzed using SOFTmax PRO software provided by the manufacturer.

Animal Administration [1]
Immunocompromised male scid mice are 6 to 8 weeks of age. The 3T3-Akt1 cell line is developed and characterized in our laboratory. The 1×106 3T3-Akt1 or 2×106 MiaPaCa-2 and PC-3 cells in 50% Matrigel are inoculated s.c. into the flank. For early treatment studies, mice are randomLy assigned to treatment groups and therapy is initiated the day after inoculation. Ten animals are assigned to each group, including controls. For established tumor studies, tumors are allowed to reach a designated size and mice are assigned to treatment groups of equal tumor size (n=10 mice per group). Tumor size is evaluated by twice weekly measurements with digital calipers. Tumor volume is estimated using the formula: V=L×W2/2. A-443654 is given s.c. in a vehicle of 0.2% HPMC. A-674563 is given orally in a vehicle of 5% dextrose.

References:
[1]. Luo Y, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Ther. 2005 Jun;4(6):977-86. [2]. Zheng J, et al. Rapamycin sensitizes Akt inhibition in malignant human breast epithelial cells. Cancer Lett. 2010 Oct 1;296(1):74-87. [3]. Gallia GL, et al. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther. 2009 Feb;8(2):386-93. [4]. Zhao Y, et al. Estrogen receptor alpha and beta regulate actin polymerization and spatial memory through an SRC-1/mTORC2-dependent pathway in the hippocampus of female mice. J Steroid Biochem Mol Biol. 2017 Nov;174:96-113.

A-443654 Dilution Calculator

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Preparing Stock Solutions of A-443654

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.5158 mL 12.5792 mL 25.1585 mL 50.317 mL 62.8962 mL
5 mM 0.5032 mL 2.5158 mL 5.0317 mL 10.0634 mL 12.5792 mL
10 mM 0.2516 mL 1.2579 mL 2.5158 mL 5.0317 mL 6.2896 mL
50 mM 0.0503 mL 0.2516 mL 0.5032 mL 1.0063 mL 1.2579 mL
100 mM 0.0252 mL 0.1258 mL 0.2516 mL 0.5032 mL 0.629 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on A-443654

A-443654 is a potent and selective inhibitor of Akt with Ki value of 160 pM [1].
The Akt kinases play important roles in cellular signal transduction and take participate in the regulation of cell transformation and tumor progression. The activities of them are usually elevated in human malignancies. A-443654 is a pan inhibitor of Akt1, 2 and 3. It binds to the ATP-binding site of Akt and inhibits the kinase activity reversibly. A-443654 shows selectivity against Akt. The inhibition ability of it for Akt is much higher than that for other kinases. It is found that A-443654 can suppress the phosphorylation of the downstream proteins of Akt while increased the Ser473 and Thr308 phosphorylation of Akt [1].
In murine FL5.12 cells stably transfected with human Akt1, 2 or 3, A-443654 inhibited the phosphorylation of GSK3 dose-dependently. A-443654 at a concentration of 0.6 μM inhibited Akt and induced G2/M accumulation in H1299 cells. In MiaPaCa-2 cells, treatment of A-443654 for 48 h resulted in a suppression of tumor proliferation with EC50 value of 100 nM. In chronic lymphocytic leukemia cells, A-443654 also inhibited the activity of Akt and induced apoptosis with EC50 value of 0.63 μM .Besides that, A-443654 was found to cause decreased phosphorylation of GSK3, FOXO3, TSC2 and mTOR in MiaPaCa-2 cells. It is also reported that A-443654 was effective in blocking the phosphorylation of 4EBP-1 and S6 protein in both T47D and LNCaP cells [1, 2, 3 and 4].
A-443654 is not oral available. In mice model with human MiaPaCa-2 pancreatic cell xenograft, the administration of A-443654 at a dose of 7.5mg/kg/d significantly inhibited tumor growth. A-443654 also inhibited tumor growth in 3T3 murine fibroblast model expressing active Akt. When using the combination of A-443654 and rapamycin in mice model with MiaPaCa-2 pancreatic cancer xenograft, the administration showed more efficacy than each monotherapy [1].
References:
1.Luo Y, Shoemaker A R, Liu X, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Molecular cancer therapeutics, 2005, 4(6): 977-986.
2.Liu X, Shi Y, Woods K W, et al. Akt inhibitor a-443654 interferes with mitotic progression by regulating aurora a kinase expression. Neoplasia, 2008, 10(8): 828-837.
3.Merce de Frias M, Iglesias-Serret D, Cosialls A M, et al. Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells. haematologica, 2009, 94(12): 1698-1707.
4.Cherrin C, Haskell K, Howell B, et al. An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo. Cancer biology & therapy, 2010, 9(7): 493-503.

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References on A-443654

Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition.[Pubmed:17334390]

Oncogene. 2007 Aug 16;26(38):5655-61.

Rapamycin, a natural product inhibitor of the Raptor-mammalian target of rapamycin complex (mTORC1), is known to induce Protein kinase B (Akt/PKB) Ser-473 phosphorylation in a subset of human cancer cell lines through inactivation of S6K1, stabilization of insulin receptor substrate (IRS)-1, and increased signaling through the insulin/insulin-like growth factor-I/phosphatidylinositol 3-kinase (PI3K) axis. We report that A-443654, a potent small-molecule inhibitor of Akt serine/threonine kinases, induces Akt Ser-473 phosphorylation in all human cancer cell lines tested, including PTEN- and TSC2-deficient lines. This phenomenon is dose-dependent, manifests coincident with Akt inhibition and likely represents an alternative, rapid-feedback pathway that can be functionally dissociated from mTORC1 inhibition. Experiments performed in TSC2-/- cells indicate that TSC2 and IRS-1 cooperate with, but are dispensable for, A-443654-mediated Akt phosphorylation. This feedback event does require PI3K activity, however, as it can be inhibited by LY294002 or wortmannin. Small interfering RNA-mediated knockdown of mTOR or Rictor, components of the rapamycin-insensitive mTORC2 complex, but not the mTORC1 component Raptor, also inhibited Akt Ser-473 phosphorylation induced by A-443654. Our data thus indicate that Akt phosphorylation and activity are coupled in a manner not previously appreciated and provide a novel mode of Akt regulation that is distinct from the previously described rapamycin-induced IRS-1 stabilization mechanism.

Akt inhibitor a-443654 interferes with mitotic progression by regulating aurora a kinase expression.[Pubmed:18670641]

Neoplasia. 2008 Aug;10(8):828-37.

Both Akt and Aurora A kinase have been shown to be important targets for intervention for cancer therapy. We report here that Compound A (A-443654), a specific Akt inhibitor, interferes with mitotic progression and bipolar spindle formation. Compound A induces G(2)/M accumulation, defects in centrosome separation, and formation of either monopolar arrays or disorganized spindles. On the basis of gene expression array studies, we identified Aurora A as one of the genes regulated transcriptionally by Akt inhibitors including Compound A. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, either by PI3K inhibitor LY294002 or by Compound A, dramatically inhibits the promoter activity of Aurora A, whereas the mammalian target of rapamycin inhibitor has little effect, suggesting that Akt might be responsible for up-regulating Aurora A for mitotic progression. Further analysis of the Aurora A promoter region indicates that the Ets element but not the Sp1 element is required for Compound A-sensitive transcriptional control of Aurora A. Overexpression of Aurora A in cells treated with Compound A attenuates the mitotic arrest and the defects in bipolar spindle formation induced by Akt inhibition. Our studies suggest that that Akt may promote mitotic progression through the transcriptional regulation of Aurora A.

Description

A-443654 is a pan-Akt inhibitor and has equal potency against Akt1, Akt2, or Akt3 within cells (Ki=160 pM).

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