GSK690693

Validation & Quality Control

Product Citations(2)

Mol Cancer Ther, 2012, 11(7), 1510-1517

J Biol Chem, 2013, 286(43), 37389-37398

Customer Reviews(1) in vivo invitation

Quality Control & MSDS

Related Compound Libraries

GSK690693 is available in the following compound libraries:

Cambridge Cancer Compound Library(96-well) Chemical Library (96-well) Inhibitor Library (96-well) Kinase Inhibitor Library (96-well)

Product Information

Compare Akt Inhibitors

Cat.No.	Product Name	Solubility (25°C)
Cat.No.	Product Name	Water	DMSO	Ethanol
S1078	MK-2206 2HCl	1 mg/mL	14 mg/mL	<1 mg/mL
S1037	Perifosine	8 mg/mL	<1 mg/mL	15 mg/mL
S1113	GSK690693	<1 mg/mL	39 mg/mL	<1 mg/mL
S2808	GDC-0068	<1 mg/mL	92 mg/mL	92 mg/mL
S2743	PF-04691502	<1 mg/mL	14 mg/mL	<1 mg/mL
S1558	AT7867	<1 mg/mL	68 mg/mL	5 mg/mL
S1117	Triciribine	<1 mg/mL	64 mg/mL	<1 mg/mL
S2635	CCT128930	<1 mg/mL	68 mg/mL	6 mg/mL
S2670	A-674563	72 mg/mL	72 mg/mL	18 mg/mL
S1556	PHT-427	<1 mg/mL	82 mg/mL	60 mg/mL
S2310	Honokiol	53 mg/mL	53 mg/mL	<1 mg/mL
S3056	Miltefosine (Hexadecylphosphocholine)	82 mg/mL	<1 mg/mL	82 mg/mL
S8019	AZD5363	<1 mg/mL	86 mg/mL	<1 mg/mL

Research Area
Research Area
GSK690693 Mechanism
GSK690693 Mechanism
AKT2, also known as protein kinase B beta, consists of an N-terminal pleckstrin homology (PH) domain, a catalytic domain and a C-terminal regulatory domain. The PH domain is involved in the binding with phosphorylated phosphatidylinositol (PIP) lipids. ^[1] There are two activation-related regulatory sites, Thr 309 in the activation loop of AKT2 kinase domain and Ser 474 in the hydrophobic motif of the C-terminal part. The catalytic domain comprises an N-terminal lobe and a larger C-terminal lobe. The ATP-binding site is located in the cleft at the interface of the two lobes, while the activation loop and the substrate binding site are in the C-terminal lobe. ^[2]
GSK690693 is a pyridylimidazole-oxadiazolyl amine. The crystal structure reveals the binding of GSK690693 in the ATP binding pocket of AKT2 kinase domain containing a S474D mutation. Specifically, GSK690693 makes a key interaction with the hinge binding region of AKT2 via a hydrogen bond between N5 of the oxadiazole moiety and the backbone NH of Ala232. Besides, an intramolecular hydrogen bond is also formed between N3 of the imidazopyridine ring and the exocyclic NH of the oxadiazole ring and keeps the two rings coplanar with each other. Simultaneously, the glycine rich loop is tucked down over the plane of the imidazopyridine ring, which improves hydrophobic interactions between AKT2 and GSK690693. In addition, the piperidinyl side chain of GSK690693 makes a hydrogen bond with the carboxylic acid side chain of Glu236 in the substrate binding area, and the alkynol-OH of GSK690693 is also involved in a hydrogen bonding network between the backbone NH of Phe294 and the side chain carboxylic acid of Glu200. These interactions all contributes to the potency of GSK690693 against AKT2. ^[3]
References
[1] Brazil DP, et al. Trends Biochem Sci. 2001, 26(11), 657-664.
[2] Calleja V, et al. J Chem Biol. 2009, 2(1), 11-25.
[3] Heerding DA, et al. J Med Chem. 2008, 51(18), 5663-5679.
Dr. Antonino Maria Sparta demonstrates a breakthrough in leukemia research by utilizing two inhibitors produced by Selleck Chemicals.

Product Description

Biological Activity Protocol Chemical Information Customer Reviews Product Citations Tech Support & FAQs

Biological Activity

Description	GSK690693 is a pan-Akt inhibitor targeting Akt1, Akt2 and Akt3 with IC50 of 2 nM, 13 nM, and 9 nM, respectively.
Targets	Akt1	Akt2	Akt3
IC50	2 nM	13 nM	9 nM ^[1]
In vitro	GSK690693 is very selective for the Akt isoforms versus the majority of kinases in other families. However, GSK690693 is less selective for members of the AGC kinase family including PKA, PrkX, and PKC isozymes with IC50 of 24 nM, 5 nM, and 2-21 nM, respectively. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively, and PAK4, 5, and 6 from the STE family with IC50 of 10 nM, 52 nM, and 6 nM, respectively. GSK690693 inhibits the phosphorylation of GSK3β in tumor cells with IC50 ranging from 43 nM to 150 nM. GSK690693 treatment leads to a dose-dependent increase in the nuclear accumulation of the transcription factor FOXO3A. GSK690693 potently inhibits the proliferation of T47D, ZR-75-1, BT474, HCC1954, MDA-MB-453, and LNCaP cells with IC50 of 72 nM, 79 nM, 86 nM, 119 nM, 975 nM, and 147 nM, respectively. GSK690693 treatment induces apoptosis at concentrations >100 nM in both LNCaP and BT474 cells. ^[1] Consistent with the role of AKT in cell survival, GSK690693 induces apoptosis in sensitive ALL cell lines. ^[2]
In vivo	A single administration of GSK690693 inhibits GSK3β phosphorylation in human breast carcinoma (BT474) xenografts in a dose- and time-dependent manner. Similarly, GSK690693 induces a reduction in phosphorylation of the Akt substrates, PRAS40, and FKHR/FKHRL1. GSK690693 also results in an acute increase in blood glucose, returning to baseline 8 to 10 hours after drug administration. Administration of GSK690693 induces reductions in phosphorylated Akt substrates in vivo, and potently inhibits the growth of human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts, with maximal inhibition of 58% to 75% at the dose of 30 mg/kg/day. ^[1] GSK690693 exhibits efficacy irrespective of the mechanism of Akt activation involved. GSK690693 is most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. ^[3]
Clinical Trials
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

In vitro kinase assays	His-tagged full-length Akt1, 2, or 3 are expressed and purified from baculovirus. Activation is 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 are incubated with GSK690693 at various concentrations at room temperature for 30 minutes before the reaction is initiated with the addition of substrate. Final reaction contains 5 nM 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 are incubated at room temperature for 45 minutes, followed by termination with Leadseeker beads in PBS containing EDTA (final concentration, 2 mg/mL beads and 75 mM EDTA). The plates are then sealed, the beads are allowed to settle for at least 5 hours, and product formation is quantitated using a Viewlux Imager.

In vitro kinase assays

His-tagged full-length Akt1, 2, or 3 are expressed and purified from baculovirus. Activation is 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 are incubated with GSK690693 at various concentrations at room temperature for 30 minutes before the reaction is initiated with the addition of substrate. Final reaction contains 5 nM 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 are incubated at room temperature for 45 minutes, followed by termination with Leadseeker beads in PBS containing EDTA (final concentration, 2 mg/mL beads and 75 mM EDTA). The plates are then sealed, the beads are allowed to settle for at least 5 hours, and product formation is quantitated using a Viewlux Imager.

Cell Assay: ^[1]

Cell lines	T47D, ZR-75-1, BT474, HCC1954, MDA-MB-453, LNCaP, etc.
Concentrations	Dissolved in DMSO, final concentrations ~30 μM
Incubation Time	72 hours
Method	Cells are plated at densities that allow untreated cells to grow logarithmically during the course of a 3-day assay. Briefly, cells are plated in 96- or 384-well plates and incubated overnight. Cells are then treated with GSK690693 (ranging from 30 μM-1.5 nM) and incubated for 72 hours. Cell proliferation is measured using the CellTiter Glo reagent. Data are analyzed using the XLFit curve-fitting tool for Microsoft Excel. IC50 values are obtained by fitting data to Eq, 2.

Animal Study: ^[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
Formulation	Formulated in either 4% DMSO/40% hydroxypropyl-β-cyclodextrin in water (pH 6.0) or 5% dextrose (pH 4.0)
Dosages	~30 mg/kg/day
Administration	Administered via i.p.

1

References

Chemical Information

Download GSK690693 SDF

Molecular Weight (MW)	425.48
Formula	C₂₁H₂₇N₇O₃
CAS No.	937174-76-0
Synonyms	N/A

Solubility (25°C) DMSO 39 mg/mL Water <1 mg/mL Ethanol <1 mg/mL
Storage	2 years -20°CPowder
	2 weeks4°Cin DMSO
	6 months-80°Cin DMSO

Chemical Name	4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-((S)-piperidin-3-ylmethoxy)-1H-imidazo[4,5-c]pyridin-4-yl)-2-methylbut-3-yn-2-ol

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Research Area

Customer Reviews (1)

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Rating

Source

Dr. Milica Pesic of Institute for Biological Research. GSK690693 purchased from Selleck

Method

Sulforhodamine B assay

Cell Lines

DLD1 cells, U87 cells, DLD1-TxR cells, U87-TxR cells

Concentrations

0-100 nM

Incubation Time

72 h

Results

GSK690693 efficacy decreased in DLD1-TxR in comparison to its sensitive counterpart - DLD1. concentration-dependent cell growth inhibition induced by GSK690693 does not differ between sensitive (U87) and resistant (U87-TxR) glioblastoma cell lines

Product Citations (2)

Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells. [Makhov PB, et al. Mol Cancer Ther 2012;11(7), 1510-1517]
PubMed: 22532600
IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. [Guo JP, et al. J Biol Chem 2013;286(43), 37389-37398]
PubMed: 21908616

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Triciribine phosphate (TCN-P, NSC-280594, API-2) is a potent Akt inhibitor with IC50 of 130 nM.
PF-04691502

PF-04691502 is an ATP-competitive, selective inhibitor of PI3K(α/β/δ/γ)/mTOR with K_i of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM, also inhibits Akt phosphorylation on T308/S473 with IC50 of 7.5 nM/3.8 nM.

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Validation & Quality Control

Product Citations(2)

Customer Reviews(1) in vivo invitation

Quality Control & MSDS

Related Compound Libraries

GSK690693 is available in the following compound libraries:

Product Information

Compare Akt Inhibitors

Research Area

GSK690693 Mechanism

Product Description

Biological Activity

Protocol(Only for Reference)

Kinase Assay: ^[1]

Cell Assay: ^[1]

Animal Study: ^[1]

References

Chemical Information

Research Area

Customer Reviews (1)

Product Citations (2)

Tech Support & FAQs

If you have any other enquiries, please leave a message.

Related Akt Inhibitors

PI3K/Akt/mTOR Pathway Products

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Product Categories

GSK690693

Validation & Quality Control

Product Citations(2)

Customer Reviews(1) in vivo invitation

Quality Control & MSDS

Related Compound Libraries

GSK690693 is available in the following compound libraries:

Product Information

Compare Akt Inhibitors

Research Area

GSK690693 Mechanism

Product Description

Biological Activity

Protocol(Only for Reference)

Kinase Assay: [1]

Cell Assay: [1]

Animal Study: [1]

References

Chemical Information

Research Area

Customer Reviews (1)

Product Citations (2)

Tech Support & FAQs

If you have any other enquiries, please leave a message.

Related Akt Inhibitors

PI3K/Akt/mTOR Pathway Products

Recently Viewed Items

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Kinase Assay: ^[1]

Cell Assay: ^[1]

Animal Study: ^[1]