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GSK690693Pan-AKT inhibitor,ATP-competitive and potent

GSK690693

Catalog No. A5072
Size Price Stock Qty
100mg $600.00 In stock

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Sample solution is provided at 25 µL, 10mM.

Quality Control

Quality Control & MSDS

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Chemical structure

GSK690693

Related Biological Data

GSK690693

Related Biological Data

GSK690693

Biological Activity

Targets Akt1 Akt2 Akt3      
IC50 2 nM 13 nM 9 nM      

Protocol

Kinase experiment [1]:

In vitro kinase assays

His-tagged full-length Akt1, 2, or 3 were expressed and purified from baculovirus. Activation was carried out with purified PDK1 to phosphorylate Thr308 and purified MK2 to phosphorylate Ser473. To more accurately measure time-dependent inhibition of Akt, activated Akt enzymes were incubated with GSK690693 at various concentrations at room temperature for 30 mins before the reaction was initiated with the addition of substrate. Final reaction contains 5 to 15 nM Akt1, 2, and 3 enzymes; 2 μM ATP; 0.15 μCi/μL[γ-33P]ATP; 1 μM Peptide (Biotin-aminohexanoicacid-ARKR-ERAYSFGHHA-amide); 10 mM MgCl2; 25 mM MOPS (pH 7.5); 1 mM DTT; 1 mM CHAPS; and 50 mM KCl. The reactions were incubated at room temperature for 45 mins, followed by termination with Leadseeker beads in PBS containing EDTA (final concentration, 2 mg/mL beads and 75 mM EDTA). The plates were then sealed, the beads were allowed to settle for at least 5 hrs, and product formation was quantitated using a Viewlux Imager.

Cell experiment [1]:

Cell lines

T47D, ZR-75-1, BT474, HCC1954, MDA-MB-453 and LNCaP cells

Preparation method

The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months.

Reaction Conditions

~ 30 μM; 72 hrs

Applications

GSK690693 potently inhibited the proliferation of T47D, ZR-75-1, BT474, HCC1954, MDA-MB-453 and LNCaP cells with the IC50 values of 72 nM, 79 nM, 86 nM, 119 nM, 975 nM, and 147 nM, respectively.

Animal experiment [1]:

Animal models

Female CD1 Swiss Nude mice injected with LNCaP, SKOV-3 or PANC1 cells, and C.B-17 SCID mice with HCC1954, MDA-MB-453 or BT474 cells

Dosage form

10, 20 or 30 mg/kg; i.p.; q.d., for 21 days

Applications

GSK690693 potently inhibited the growth of human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts, with maximal inhibition ranging from 58% to 75% at the dose of 30 mg/kg/day.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Rhodes N, Heerding DA, Duckett DR et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 2008; 68: 2366-2374.

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Chemical Properties

Cas No. 937174-76-0 SDF Download SDF
Chemical Name 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol
Canonical SMILES CCN1C2=C(C(=NC=C2OCC3CCCNC3)C#CC(C)(C)O)N=C1C4=NON=C4N
Formula C21H27N7O3 M.Wt 425.48
Solubility Soluble in DMSO > 10 mM Storage Store at -20°C
General tips No
Shipping Condition No

Background

GSK690693 is a pan-Akt inhibitor targeting Akt1, 2, 3 with IC50 values of 2, 13 and 9 nM, respectively [1, 2]. In addition, it also inhibits AMPK (IC50=50 nM), DAPK3 (IC50=81 nM), PAK4, 5, and 6 (IC50=10, 52, 6 nM), as well as the members of AGC kinase family including PKA (IC50=24 nM), PrkX (IC50=5 nM), and PKC isozymes (IC50=2-21 nM) [1]. GSK690693 reversibly occupies the ATP binding pocket of the kinase domain and competes with ATP as shown by crystal structure [2]. It blocks the phosphorylation of downstream targets of ATK in a dose-dependent manner [1].

GSK690693 has shown potential anti-tumor activity both in vitro and in vivo.

Akt plays an important role in regulation of cell cycle progression and tumor cell survival. GSK690693 reduced proliferation and led to apoptosis in tumor cells with potency correlated to the inhibited activity of Akt kinase [1, 3]. In xenografts models, it inhibited the growth of SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast tumors [1]. It delayed the tumor progression in transgenic mice expressing a constitutively activated form of Akt [4]. GSK690693 has been tested in phase I clinical trials [5].

References:
[1]Rhodes N, Heerding DA, Duckett DR et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 2008; 68: 2366-2374.[2]Heerding DA, Rhodes N, Leber JD et al. Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H- imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J Med Chem 2008; 51: 5663-5679.[3]Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 2009; 113: 1723-1729.[4]Altomare DA, Zhang L, Deng J et al. GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt. Clin Cancer Res 2010; 16: 486-496.[5]Pal SK, Reckamp K, Yu H, Figlin RA. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2010; 19: 1355-1366.