1233339-22-4

1233339-22-4 - Names and Identifiers

Name	(R)-4-(2-(1H-indol-4-yl)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine
Synonyms	AZ20 AZ-20 AZ 20 CS-1335 (3R)-4-[2-(3H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine (R)-4-(2-(1H-indol-4-yl)-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine 4-[4-[(3R)-3-Methyl-4-morpholinyl]-6-[1-(methylsulfonyl)cyclopropyl]-2-pyrimidinyl]-1H-indole 1H-Indole, 4-[4-[(3R)-3-methyl-4-morpholinyl]-6-[1-(methylsulfonyl)cyclopropyl]-2-pyrimidinyl]- 4-[4-[(3R)-3-Methyl-4-morpholinyl]-6-[1-(methylsulfonyl)cyclopropyl]-2-pyrimidinyl]-1H-indole AZ20 AZ20 4-[4-[(3R)-3-Methyl-4-morpholinyl]-6-[1-(methylsulfonyl)cyclopropyl]-2-pyrimidinyl]-1H-indole
CAS	1233339-22-4

1233339-22-4 - Physico-chemical Properties

Molecular Formula	C21H24N4O3S
Molar Mass	412.51
Density	1.42±0.1 g/cm3(Predicted)
Boling Point	634.6±55.0 °C(Predicted)
Solubility	DMSO:50mg/ml
Appearance	solid
Color	Off-white
pKa	15.65±0.30(Predicted)
Storage Condition	-20°
Stability	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
Use	AZ20 is an effective and selective ATR inhibitor with an IC50 value of 5 nM; it can also inhibit mTOR activity with an IC50 value of 38 nM.
Target	ATR mTOR
In vitro study	AZ20 shows good selectivity for all PI3K subtypes together with ATM and DNA-PK. In Vitro, AZ20 reduced pChk1 Ser345,pChk1 Ser317 and pChk1 Ser296 levels in a concentration-dependent manner. Prolonged treatment time of AZ20 increased γH2AX nuclear staining, which is an expression of replicative pressure. This is associated with S-phase arrest and increased phosphorylation of histone H3. AZ20 induces growth inhibition and cell death in vitro and its activity is distinct from that of other cytotoxic drugs. The cytotoxic effect of AZ2 is increased when combined with an ATM inhibitor KU-60019.
In vivo study	Oral administration of AZ20,25 mg/kg twice daily, or 50 mg/kg once daily for 13 days significantly inhibited tumor growth in female nude mice with LoVo tumors. This is related to the widespread persistent elevation of nuclear staining of γH2AX in xenograft tissues, but at therapeutic doses resulting in a transient elevation in mouse bone marrow, indicating the favorable therapeutic properties of az20. AZ20 is an evaluation of drug-drug potential interactions (DDI), specifically inhibition of cytochrome P450 enzymes. AZ20(10 μm) inhibited cytochrome 3A4 mediated midazolam metabolism by 50%. AZ20 has good bioavailability in the rat PK study.

1233339-22-4 - Reference

Reference

1: Foote KM, Blades K, Cronin A, Fillery S, Guichard SS, Hassall L, Hickson I, Jacq X, Jewsbury PJ, McGuire TM, Nissink JW, Odedra R, Page K, Perkins P, Suleman A, Tam K, Thommes P, Broadhurst R, Wood C. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem. 2013 Mar 14;56(5):2125-38. doi: 10.1021/jm301859s. Epub 2013 Mar 1. PubMed PMID: 23394205.

1233339-22-4 - Preparation solution concentration reference

	1mg	5mg	10mg
1 mM	2.424 ml	12.121 ml	24.242 ml
5 mM	0.485 ml	2.424 ml	4.848 ml
10 mM	0.242 ml	1.212 ml	2.424 ml
5 mM	0.048 ml	0.242 ml	0.485 ml

Last Update：2024-01-02 23:10:35

1233339-22-4 - Cell Experiment

AZ20 is dissolved in 100% DMSO. Compound dose ranges are created by diluting in 100% DMSO and then further into assay medium (EMEM, 10% FCS, 1% glutamine) using a Labcyte Echo acoustic dispensing instrument. Cells are plated in 384-well Costar plates at 9×104 cells per mL in 40 μL of EMEM, 10% FCS, 1% glutamine and grown for 24 h. Following addition of compound the cells are incubated for 60 min. A final concentration of 3 μM 4NQO (prepared in 100% DMSO) is then added using the Labcyte Echo, and the cells are incubated for a further 60 min. The cells are fixed by adding 40 μL of 3.7% v/v formaldehyde solution for 20 min. After removal of fix, cells are washed with PBS and permeabilized in 40 μL of PBS containing 0.1% Triton X-100. The cells are then washed, and 15 μL primary antibody solution (pChk1 Ser345) is added. The plates are incubated at 4°C overnight. The primary antibody is then washed off, and 20 μL of secondary antibody solution and 1 μM Hoechst 33258 added for 90 min at room temperature. The plate

Last Update：2023-08-16 21:32:38

1233339-22-4 - Reference Information

biological activity	AZ20 is a potent and selective inhibitor of ATR with an IC50 of 5 nM..
characteristics	AZ20 is the first reported inhibitor of ATR protein kinase showing inhibition of tumor growth in vivo.

Last Update：2024-04-09 21:04:16