GSK2334470

製品コードS7087 バッチS708707

化学情報

	Synonyms	N/A	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₅H₃₄N₈O
	分子量	462.59	CAS No.	1227911-45-6
Solubility (25°C)*	体外	DMSO	50 mg/mL (108.08 mM)
		Ethanol	6 mg/mL (12.97 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

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生物活性

製品説明	GSK2334470 is a novel PDK1 inhibitor with IC50 of ~10 nM in a cell-free assay, with no activity at other close related AGC-kinases.
in vitro	GSK2334470 inhibits PDK1 from activating full-length Akt1 in the presence of PtdIns(3,4,5)P₃-containing lipid vesicles or a mutant of Akt1 lacking the PH domain (ΔPH-Akt1) with IC50 of ~10 nM. GSK2334470 also similarly inhibits PDK1 from phosphorylating the PDKtide peptide substrate with IC50 of ~10 nM. GSK2334470 (0.1 μM–0.3 μM) induces significant dose-dependent inhibition of endogenous NDRG1 with over 50% reduction in phosphorylation in HEK-293 cells. GSK2334470 (30 nM) induces a significant dose-dependent inhibition of the T-loop phosphorylation of each SGK isoform in HEK-293 cells. GSK2334470 (1 μM) inhibits hydrophobic motif phosphorylation of S6K1 to a similar extent as T-loop phosphorylation in HEK-293 cells. GSK2334470 (3 μM) also suppresses S6K1 activity and phosphorylation induced by IGF1 stimulation of serum-starved HEK-293 cells. GSK2334470 (3 μM) markedly inhibits the phosphorylation of several Akt substrates [FoxO (forkhead box O), GSK3 and PRAS40]. GSK2334470 (3 μM) also induces near maximal inhibition of Akt1 activity and phosphorylation within 5 min, and Akt substrate phosphorylation (FoxO, GSK3 and PRAS40) is inhibited at a slightly later time point (10 min). GSK2334470 (0.3 μM) significantly inhibits phosphorylation of Akt or PRAS40/GSK3 in PDK1K^465E/K465E knock-in but not wild-type ES cells. GSK2334470 (1 μM) effectively suppresses SGK1 activity as judged by the inhibition of NDRG1 phosphorylation in U87 glioblastoma cells. GSK2334470 (1 μM) also potently suppresses activation of S6K1 (Figure 7B) as well as SGK1 in MEF (mouse embryonic fibroblast) cells. GSK2334470 (0.1 μM) induces ~50% inhibition of RSK2 activity in HEK-293 cells. ^[1] GSK2334470 (30 µM) suppresses U46619 induced Ca²⁺-sensitized force in α-toxin permeabilized rabbit pulmonary artery SM. GSK2334470 (30 µM) results in a significant decrease in the contractile force in response to [Ca²⁺]. ^[2] GSK2334470 (1 μM) results in total abrogation of the EGF-induced intracellular calcium increase and inositol phosphates accumulation in MDA-MB-231 cells. GSK2334470 (1 μM) inhibits PLCγ1 Tyr783 phosphorylation in MDA-MB-231 cells. ^[3]
in vivo	GSK2334470 is a highly specific and potent inhibitor of PDK1.

製品説明

GSK2334470 is a novel PDK1 inhibitor with IC50 of ~10 nM in a cell-free assay, with no activity at other close related AGC-kinases.

in vitro

GSK2334470 inhibits PDK1 from activating full-length Akt1 in the presence of PtdIns(3,4,5)P₃-containing lipid vesicles or a mutant of Akt1 lacking the PH domain (ΔPH-Akt1) with IC50 of ~10 nM. GSK2334470 also similarly inhibits PDK1 from phosphorylating the PDKtide peptide substrate with IC50 of ~10 nM. GSK2334470 (0.1 μM–0.3 μM) induces significant dose-dependent inhibition of endogenous NDRG1 with over 50% reduction in phosphorylation in HEK-293 cells. GSK2334470 (30 nM) induces a significant dose-dependent inhibition of the T-loop phosphorylation of each SGK isoform in HEK-293 cells. GSK2334470 (1 μM) inhibits hydrophobic motif phosphorylation of S6K1 to a similar extent as T-loop phosphorylation in HEK-293 cells. GSK2334470 (3 μM) also suppresses S6K1 activity and phosphorylation induced by IGF1 stimulation of serum-starved HEK-293 cells. GSK2334470 (3 μM) markedly inhibits the phosphorylation of several Akt substrates [FoxO (forkhead box O), GSK3 and PRAS40]. GSK2334470 (3 μM) also induces near maximal inhibition of Akt1 activity and phosphorylation within 5 min, and Akt substrate phosphorylation (FoxO, GSK3 and PRAS40) is inhibited at a slightly later time point (10 min). GSK2334470 (0.3 μM) significantly inhibits phosphorylation of Akt or PRAS40/GSK3 in PDK1K^465E/K465E knock-in but not wild-type ES cells. GSK2334470 (1 μM) effectively suppresses SGK1 activity as judged by the inhibition of NDRG1 phosphorylation in U87 glioblastoma cells. GSK2334470 (1 μM) also potently suppresses activation of S6K1 (Figure 7B) as well as SGK1 in MEF (mouse embryonic fibroblast) cells. GSK2334470 (0.1 μM) induces ~50% inhibition of RSK2 activity in HEK-293 cells. ^[1]

GSK2334470 (30 µM) suppresses U46619 induced Ca²⁺-sensitized force in α-toxin permeabilized rabbit pulmonary artery SM. GSK2334470 (30 µM) results in a significant decrease in the contractile force in response to [Ca²⁺]. ^[2]

GSK2334470 (1 μM) results in total abrogation of the EGF-induced intracellular calcium increase and inositol phosphates accumulation in MDA-MB-231 cells. GSK2334470 (1 μM) inhibits PLCγ1 Tyr783 phosphorylation in MDA-MB-231 cells. ^[3]

in vivo

GSK2334470 is a highly specific and potent inhibitor of PDK1.

プロトコル(参考用のみ)

キナーゼアッセイ	Kinase activity assays
キナーゼアッセイ	Endogenous Akt, S6K and RSK are immunoprecipitated from 0.1 mg to 1 mg of cell lysate for 2 hours at 4℃ on a vibrating platform using 3 μg–5 μg of the indicated antibodies. For the SGK activity assays, 150 μg of transfected lysate is incubated with 5 μg of glutathione–Sepharose for 3 hours at 4℃. The immunoprecipitates are washed twice with lysis buffer containing 0.5 mM NaCl, followed by two washes with kinase buffer. Kinase reactions are initiated by a reaction mixture to bring the final concentrations of the reaction components to 0.1 mM [γ-³²P]ATP (~200 c.p.m./pmol), 5 mM magnesium acetate, 0.1% 2-mercaptoethanol and 30 mM Crosstide peptide (GRPRTSSFAEGKK). Reactions are carried out for 20 min at 30℃ on a vibrating platform and stopped by spotting the reactions on to P81 phosphocellulose paper. Cerenkov counting is done after washing the papers in phosphoric acid, rinsing in acetone and air-drying. One unit of activity is defined as that which catalysed the incorporation of 1 nmol of [³²P]phosphate into the substrate over 1 hour.
細胞アッセイ	細胞株	MDA-MB-231 cells
	濃度	1 µM
	反応時間	30 minutes
	実験の流れ	Cells were incubated with 1 µM of GSK2334470 for 30 minutes. Cells treated with DMSO were used as control.
動物実験	動物モデル	Nude mice
	投薬量	100 mg/kg
	投与方法	i.p.

参考

[4] Scortegagna M, et al. Oncogene. 2014 Aug 21;33(34):4330-9.

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カスタマーフィードバック

: Data from [Data independently produced by , , Oncotarget, 2016, 6(7):5134-46.]

: Data from [Data independently produced by , , PLoS One, 2017, 12(2):e0171221]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Disruption of Autophagic Flux and Treatment with the PDPK1 Inhibitor GSK2334470 Synergistically Inhibit Renal Cell Carcinoma Pathogenesis [ J Cancer, 2024, 15(5):1429-1441]	PubMed: 38356720
A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors [ Cell Rep, 2022, 38(11):110522]	PubMed: 35294890
Mannan-Binding Lectin Reduces Epithelial-Mesenchymal Transition in Pulmonary Fibrosis via Inactivating the Store-Operated Calcium Entry Machinery [ J Innate Immun, 2022, 1-13]	PubMed: 35671705
Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional [ Nat Commun, 2021, 12(1):4566]	PubMed: 34315881
The 3-phosphoinositide-dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites [ PLoS Biol, 2021, 19(12):e3001483]	PubMed: 34879056
PDK1 is a negative regulator of axon regeneration [ Mol Brain, 2021, 14(1):31]	PubMed: 33579325
SOX2 enhances cell survival and induces resistance to apoptosis under serum starvation conditions through the AKT/GSK-3β signaling pathway in esophageal squamous cell carcinoma [ Oncol Lett, 2021, 21(4):269]	PubMed: 33717266
A Non-canonical PDK1-RSK Signal Diminishes Pro-caspase-8-Mediated Necroptosis Blockade [ Mol Cell, 2020, 80(2):296-310.e6]	PubMed: 32979304
PDK1-AKT signaling pathway regulates the expression and function of cardiac hyperpolarization-activated cyclic nucleotide-modulated channels. [ Life Sci, 2020, 250:117546]	PubMed: 32184125
Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities. [ Nat Cell Biol, 2019, 21(6):778-790]	PubMed: 31160710

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人間や獣医の診断であるか治療的な使用のためにでない。

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