A-674563 HCl

製品コードS2670 バッチS267002

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	C₂₂H₂₂N₄O.CIH
	分子量	394.9	CAS No.	2070009-66-2
Solubility (25°C)*	体外	DMSO	72 mg/mL (182.32 mM)
		Water	72 mg/mL (182.32 mM)
		Ethanol	18 mg/mL (45.58 mM)
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	A-674563 HCl is an Akt1 inhibitor with K_i of 11 nM in cell-free assays, modest potent to PKA and >30-fold selective for Akt1 over PKC.
in vitro	A-674563 HCl is achieved from A-443654 by replacing the indole with a phenyl moiety and getting oral activity. A-674563 slows proliferation of tumor cells with EC50 of 0.4 μM. ^[1] A-674563 does not inhibit Akt phosphorylation per se, but blocks the phosphorylation of Akt downstream targets in a dose-dependent manner. A-674563 induced Akt blockade results in decreased STS cell downstream target phosphorylation and tumor cell growth inhibiton. A-674563 induces G2 cell cycle arrest and apoptosis in STS cells. ^[2]
in vivo	20 mg/kg A-674563 increases plasma insulin in an oral glucose tolerance test. A-674563 shows no significant monotherapy tumor inhibitory activity; the efficacy of the combination therapy is significantly improved compared to paclitaxel monotherapy. ^[1] A674563-treated (20 mg/kg/bid, p.o.) mice exhibits slower tumor growth and more than 50% decrease in the tumor volume at the termination of the study compared with that in control group. ^[2] A-674563 is identified to have drastically improved PK profile with oral bioavailability of 67% in mouse, but is 70-fold less active than A-443654. ^[3]
特徴	Orally bioavailable compound (achieved by replacing indole of A-443654 with phenyl moiety) and somewhat less selective for Akt over PKA than A-443654.

プロトコル(参考用のみ)

キナーゼアッセイ	Akt Kinase Assay
キナーゼアッセイ	The kinase assay uses His-Akt1 and a biotinylated mouse Bad peptide as substrate. The kinase assay is carried out at room temperature for 30 minutes in 50 μL of reaction buffer [20 mM HEPES, pH 7.5, 10 mM MgCl₂, 0.1% (w/v) Triton X-100, 5 μM ATP (K_m = 40 μM), 5 μM peptide (K_m = 15 μM), 1 mM DTT, 60 ng of Akt1, and 0.5 μCi of [γ-³³P]ATP] in the presence of different concentrations of A-674563. Each reaction is stopped by adding 50 μL of termination buffer (0.1 M EDTA, pH 8.0, and 4 M NaCl). The biotinylated Bad peptides are immobilized on streptavidin-coated FLASH plates. Afterbeing washed with PBS-Tween 20 (0.05%), the ³³P phosphopeptide captured on the FLASH plates is measured with a TopCount Packard Instruments γ counter.
細胞アッセイ	細胞株	MiaPaCa-2 cells
	濃度	0-30 μM
	反応時間	48 hours
	実験の流れ	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 M) 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 fmax Fluorescence 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.
動物実験	動物モデル	Fasted mice
	投薬量	20 or 100 mg/kg
	投与方法	A-674563 is administered 30 minutes before the 1 g/kg glucose challenge.

参考

カスタマーフィードバック

: , 2012, Lee lay hoon from National University of Singapore

: , , Cancer Cell Int, 2017, 17:27

: Data from [Data independently produced by , , Oncotarget, 2016, 7(3):3297-316]

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 lysosomal nutrient sensing scaffold contributes to pathogenesis of a fatal neurodegenerative lysosomal storage disease [ J Biol Chem, 2024, 300(2):105641]	PubMed: 38211816
Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle [ Nat Commun, 2023, 14(1):886]	PubMed: 36797255
Functional restoration of lysosomes and mitochondria through modulation of AKT activity ameliorates senescence [ Exp Gerontol, 2023, 173:112091]	PubMed: 36657533
Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function [ Sci Adv, 2023, 9(1):eade1694]	PubMed: 36608116
Integrative analysis of drug response and clinical outcome in acute myeloid leukemia [ Cancer Cell, 2022, S1535-6108(22)00312-9]	PubMed: 35868306
Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy [ Nat Commun, 2022, 13-1:6045]	PubMed: 36229454
Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division [ Nat Commun, 2022, 13(1):668]	PubMed: 35115540
Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening [ Cancers (Basel), 2022, 14(6)1575]	PubMed: 35326726
Akt isoforms differentially provide for chemoresistance in prostate cancer [ Cancer Biol Med, 2021, j.issn.2095-3941.2020.0747]	PubMed: 34591413
Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma. [ Sci Signal, 2020, 13(619)]	PubMed: 32071169

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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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