AZ20

製品コードS7050 バッチS705001

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	C₂₁H₂₄N₄O₃S
	分子量	412.51	CAS No.	1233339-22-4
Solubility (25°C)*	体外	DMSO	83 mg/mL (201.2 mM)
		Ethanol	3 mg/mL (7.27 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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	AZ20 is a novel potent and selective inhibitor of ATR kinase with IC50 of 5 nM in a cell-free assay, 8-fold selectivity over mTOR.
in vitro	AZ20 shows good selectivity against all of the PI3K isoforms together with ATM and DNA-PK. ^[2] In vitro, AZ20 decreases pChk1 Ser345, pChk1 Ser317 and pChk1 Ser296 levels in a concentration-dependent manner. Prolonged exposure with AZ20 increases γH2AX pan-nuclear staining, indicative of replication stress. This is associated with S-phase arrest and increase in phospho-histone H3. AZ20 induces growth inhibition and cell death in vitro and its profile of activity is distinct from other cytotoxic agents. The cytotoxic effect of AZ20 can be increased in combination with the selective ATM inhibitor KU-60019. ^[1]
in vivo	Female nude mice bearing LoVo tumors are treated with AZ20 orally at a dose of 25 mg/kg twice daily or 50 mg/kg once daily for 13 days, led to significant tumor growth inhibition. ^[2] This is associated with a persistent elevation of γH2AX pan-nuclear staining in xenograft tissue, but a transient increase in mouse bone marrow at therapeutic doses, suggesting a favourable therapeutic index. ^[1] AZ20 is assessed for drug−drug interaction (DDI) potential specifically from inhibition of cytochrome P450 enzymes. AZ20 is found to inhibit the cytochrome 3A4-mediated metabolism of midazolam by 50% at 10 μM. AZ20 has respectable bioavailability in a low dose rat PK study. ^[2]
特徴	ATR-selective inhibitor with high permeability and good stability.

プロトコル(参考用のみ)

キナーゼアッセイ	ATR Kinase Assay
キナーゼアッセイ	ATR for use in the in vitro enzyme assay is obtained from HeLa nuclear extract by immunoprecipitation with rabbit polyclonal antiserum raised to amino acids 400−480 of ATR contained in the following buffer: 25 mM HEPES (pH 7.4), 2 mM MgCl₂, 250 mM NaCl, 0.5 mM EDTA, 0.1 mM Na₃VO₄, 10% v/v glycerol, and 0.01% v/v Tween 20. ATR-antibody complexes are isolated from nuclear extract by incubating with protein A-Sepharose beads for 1 h and then through centrifugation to recover the beads. In the well of a 96-well plate, 10 μL ATR-containing Sepharose beads are incubated with 1 μg of substrate glutathione S-transferase−p53N66 in ATR assay buffer (50 mM HEPES (pH 7.4), 150 mM NaCl, 6 mM MgCl₂, 4 mM MnCl₂, 0.1 mM Na₃VO₄, 0.1 mM DTT, and 10% (v/v) glycerol) at 37 °C in the presence or absence of inhibitor. After 10 min with gentle shaking, ATP is added to a final concentration of 3 μM and the reaction continued at 37 °C for an additional 1 h. The reaction is stopped by addition of 100 μL of PBS, and the reaction is transferred to a white opaque glutathione coated 96-well plate and incubated overnight at 4 °C. This plate is then washed with PBS/0.05% (v/v) Tween 20, blotted dry, and analyzed by a standard ELISA technique with a phosphoserine 15 p53 antibody. The detection of phosphorylated glutathione S-transferase−p53N66 substrate is performed in combination with a goat anti-mouse horseradish peroxidase-conjugated secondary antibody. Enhanced chemiluminescence solution is used to produce a signal, and chemiluminescent detection is carried out via a TopCount plate reader. The resulting calculated % enzyme activity is then used to determine the IC50 values for the compounds.
動物実験	動物モデル	LoVo colorectal adenocarcinoma xenografts
	投薬量	25 mg/kg twice daily and 50 mg/kg once daily
	投与方法	orally

参考

カスタマーフィードバック

: Data from [Data independently produced by , , Molecular Oncology, 2016, 1-13.]

: Data from [Data independently produced by , , Sci Rep, 2017, 7:41950]

: Data from [Data independently produced by , , Oncotarget, 2016, 7(18):25885-901]

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：

OTUD5 limits replication fork instability by organizing chromatin remodelers [ Nucleic Acids Res, 2023, 51(19):10467-10483]	PubMed: 37713620
Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET [ Cell Death Differ, 2023, 10.1038/s41418-023-01167-4]	PubMed: 37142656
OTUD5 limits replication fork instability by organizing chromatin remodelers [ Nucleic Acids Res, 2023, gkad732]	PubMed: 37713620
ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms [ Cell Rep, 2023, 42(7):112792]	PubMed: 37454295
Adeno-Associated Virus Monoinfection Induces a DNA Damage Response and DNA Repair That Contributes to Viral DNA Replication [ mBio, 2023, e0352822.]	PubMed: 36719192
Inhibition of DNA-dependent protein kinase catalytic subunit boosts rAAV transduction of polarized human airway epithelium [ Mol Ther Methods Clin Dev, 2023, 31:101115]	PubMed: 37841417
ATR activation by Cr-DNA damage is a major survival response establishing late S and G2 checkpoints after Cr-VI) exposure [ Toxicol Appl Pharmacol, 2023, 477:116696]	PubMed: 37734571
Comprehensive mapping of cell fates in microsatellite unstable cancer cells support dual targe6ng of WRN and ATR [ bioRxiv, 2023, 2023.07.28.550976]	PubMed: 37662356
The TRESLIN-MTBP complex couples completion of DNA replication with S/G2 transition [ Mol Cell, 2022, 82(18):3350-3365.e7]	PubMed: 36049481
Phosphoproteomics of ATR signaling in mouse testes [ Elife, 2022, 11e68648]	PubMed: 35133275

長期の保管のために-20°Cの下で製品を保ってください。

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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