AT9283

Catalog No.S1134

Molecular Weight(MW): 381.43

AT9283 is a potent JAK2/3 inhibitor with IC50 of 1.2 nM/1.1 nM in cell-free assays; also potent to Aurora A/B, Abl(T315I). Phase 2.

3 Customer Reviews

HEL cells were treated with 0.5, 1 or 5 uM of AT9283 or left untreated for 3 hrs. The expression and phosphorylation state of STAT5 (P-STAT5) and Jak2 (P-Jak2) was assessed by Western blot immunodetection.

J Cell Mol Med 2013 17(2), 265-76. AT9283 purchased from Selleck.

AM-005 inhibits the growth of HT29 cells in vivo. The tumor volume was measured after intragastric administration of AM-005 (15 mg/kg or 25 mg/kg). The 25 mg/kg AT9283 was used as a positive control. The results are the mean tumor volume盨D for groups of n = 8.

Drug Development Reseach 2013 272-281. AT9283 purchased from Selleck.
HEL cells were treated for 3 hours with the indicated concerntrations of AT9283. AT9283 inhibitors Jak2-V617F mediated signal transduction at submicromolar concentrations in intact cells . At concentrations of 490 nm the Jak2-V617F inhibition is almost complete and has reached almost background levels (for background STAT5 phosphorylation see 4400nm)

Dr. Claude Haan and Catherine Rolvering of Universite du Luxembourg. AT9283 purchased from Selleck.

Purity & Quality Control

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Biological Activity

Description

AT9283 is a potent JAK2/3 inhibitor with IC50 of 1.2 nM/1.1 nM in cell-free assays; also potent to Aurora A/B, Abl(T315I). Phase 2.

Targets

JAK3 ^[1] (Cell-free assay)	JAK2 ^[1] (Cell-free assay)	Aurora A ^[1] (Cell-free assay)	Aurora B ^[1] (Cell-free assay)	Abl1 (T315I) ^[1] (Cell-free assay)	View More
1.1 nM	1.2 nM	~3.0 nM	~3.0 nM	4 nM	View More

In vitro

AT9283 leads to a clear polyploid phenotype by inhibiting the activity of Aurora B kinase in HCT116 cells with IC50 of 30 nM. Furthermore, AT9283 also produces the potent inhibition on HCT116 colony formation. ^[1]

Cell Data

Cell Lines	Assay Type	Incubation Time	Activity Description	PMID
HCT116 cells	NHTJ[mdEgXSxdH;4bYPDqGG\|c3H5	NYTCbnZ2OTBvMUSg[IF6ew>?	MULDfZRwfG:6aXPpeJkh[WejaX7zeEBpfW2jbjDIR3QyOTZiY3XscJMh[XO\|ZYPz[YQh[XNiboXtZoVzKG:oIHPvcI9vcWW\|IHHmeIVzKDFyIITvJFE1KGSjeYOgZpkh[2:ub375JIZwem2rbnegZZN{[XluIFnDOVA:OC5yMUKg{txO	M3TROlE6OTR\|NU[3
HT-29 cells	M1zaXmZ2dmO2aX;uJIF{e2G7	M3OzbVczKGh?	NFK2fVZCdnSrdIXtc5Ih[WO2aY\peJkh[WejaX7zeEBpfW2jbjDIWE0zQSClZXzsd{Bi\nSncjC3NkBpenNiYomgUXRVKGG\|c3H5MEBKSzVyPUCuN\|g{KM7:TR?=	NIfVTIkzOzZ4NEC5PS=>
A549 cells	MUTGeY5kfGmxbjDhd5NigQ>?	M3TB[FczKGh?	NUXPZnFxSW62aYT1cY9zKGGldHn2bZR6KGGpYXnud5QhcHWvYX6gRVU1QSClZXzsd{Bi\nSncjC3NkBpenNiYomgUXRVKGG\|c3H5MEBKSzVyPUCuOVEzKM7:TR?=	M2jPdlI{PjZ2MEm5
LoVo cells	NHu3WpZHfW6ldHnvckBie3OjeR?=	MmnHO\|IhcA>?	NIDuSWlCdnSrdIXtc5Ih[WO2aY\peJkh[WejaX7zeEBpfW2jbjDMc3ZwKGOnbHzzJIFnfGW{IEeyJIhzeyCkeTDNWHQh[XO\|YYmsJGlEPTB;MD61OVMh\|ryP	M1TMblI{PjZ2MEm5
K562 cells	NYPZOWozTnWwY4Tpc44h[XO\|YYm=	MYK3NkBp	NXPpR2p7SW62aYT1cY9zKGGldHn2bZR6KGGpYXnud5QhcHWvYX6gT\|U3OiClZXzsd{Bi\nSncjC3NkBpenNiYomgUXRVKGG\|c3H5MEBKSzVyPUGuOkDPxE1?	MUWyN\|Y3PDB7OR?=
U937 cells	NX[wXGJTTnWwY4Tpc44h[XO\|YYm=	M1zhSVczKGh?	MX3BcpRqfHWvb4KgZYN1cX[rdImgZYdicW6\|dDDoeY1idiCXOUO3JINmdGy\|IHHmeIVzKDd{IHjyd{BjgSCPVGSgZZN{[Xl?	Mo\FNlM3PjRyOUm=

... Click to View More Cell Line Experimental Data

In vivo

In HCT116 human colon carcinoma xenograft bearing mice, AT9283 treatment (15 mg/kg and 20 mg/kg) for 16 days results in a significant tumor growth inhibition of 67% and 76%, respectively. In addition, AT9283 also exhibits a significantly longer half-life in tumors(2.5 hours) compared with plasma (0.5 hour) and modest oral bioavailability in mice (Fp.o. = 24%). ^[1]

Protocol

Kinase Assay: ^[1]	+ Expand Aurora A and Aurora B Kinase Assays: Assays for Aurora A and B are performed in a DELFIA format. Aurora A enzyme is incubated with AT9283 and 3 μM cross-tide substrate (biotin-CGPKGPGRRGRRRTSSFAEG) in 10 mM MOPS, pH 7, 0.1 mg/mL BSA, 0.001% Brij-35, 0.5% glycerol, 0.2 mM EDTA, 10 mM MgCl₂, 0.01% β-mercaptoethanol, 15 μM ATP, and 2.5% DMSO. Aurora B enzyme is incubated with AT9283, 3 μM of the above substrate in 25 mM Tris, pH 8.5, 5 mM MgCl₂, 0.1 mg/mL BSA, 0.025% Tween-20, 1 mM DTT, 15 μM ATP, and 2.5% DMSO. Reactions are allowed to proceed for 60 minutes and 45-90 minutes for Aurora A and Aurora B, respectively, before quenching with EDTA. The reaction mixtures are then transferred to a neutravidin-coated plate, and phosphorylated peptide is quantified by means of a phospho-specific antibody and a europium labeled secondary antibody using time-resolved fluorescence (excitation, 337 nm; emission, 620 nm). IC50 values for the control compounds are 92 nM (Aurora A assay) and 17 nM (Aurora B).
Cell Research: ^[1]	+ Expand Cell lines: HCT 116 cells Concentrations: 1 nM - 10 μM Incubation Time: 72 hours Method: HCT 116 cells are cultured in DMEM + 10% FBS + GLUTAMAX I. Black 96-well flat-bottomed (clear) tissue culture treated plates are seeded in 200 μL of medium and incubated for approximately 16 hours at 37°C in a humidified atmosphere of 5% CO₂ in air. Cells are treated with test compound at nine different concentrations (spanning 1 nM to 10 μM, plus DMSO vehicle control) and then incubated for 72 hours. Polyploidy morphological observations of the cells are then noted. The concentration of AT9283 required to produce a distinct polyploid phenotype is reported. Cells are seeded at a concentration of 75−100 cells/mL relevant culture media onto 6- or 24-well tissue culture plates and allowed to recover for 16 hours. Test compound (11 concentrations spanning 0.1 nM to 10 μM) or vehicle control (DMSO) is added to duplicate wells to give a final DMSO concentration of 0.1%. Following compound addition, colonies are allowed to grow between 10 and 14 days for optimum discrete colony counting. Colonies are fixed in 2 mL of Carnoys fixative (25% acetic acid, 75% MeOH) and stained in 2 mL of 0.4% w/v crystal violet. The numbers of colonies in each well is counted. IC50 values are calculated by sigmoidal dose-response (variable slope) IC50 curves using Prism Graphpad software. (Only for Reference)
Animal Research: ^[1]	+ Expand Animal Models: HCT116 cells are injected s.c. Into the hind flank of male BALB/c mice. Formulation: Belinostat is dissolved in 10% DMSO, 20% water, 70% hydroxypropyl- β-cyclodextrin (25% w/v aq). Dosages: 15 mg/kg and 20 mg/kg Administration: Administered via i.p. (Only for Reference)

References

Solubility (25°C)

In vitro	DMSO	76 mg/mL (199.25 mM)
	Ethanol	38 mg/mL (99.62 mM)
	Water	Insoluble
In vivo	Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 2% DMSO+30% PEG 300+ddH2O For best results, use promptly after mixing.	5mg/mL

* 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.

Chemical Information Download AT9283 SDF

Molecular Weight	381.43
Formula	C₁₉H₂₃N₇O₂
CAS No.	896466-04-9
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	N/A

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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2018-10-19)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01431664	Completed	Leukemia	Cancer Research UK	September 2011	Phase 1
NCT01145989	Completed	Multiple Myeloma	NCIC Clinical Trials Group\|Canadian Cancer Trials Group	June 2010	Phase 2
NCT00985868	Active not recruiting	Unspecified Childhood Solid Tumor Protocol Specific	Cancer Research UK	September 2009	Phase 1
NCT00443976	Completed	Non-Hodgkins Lymphoma\|Unspecified Adult Solid Tumor Protocol Specific	NCIC Clinical Trials Group\|Canadian Cancer Trials Group	January 2007	Phase 1
NCT00522990	Terminated	Acute Myeloid Leukemia\|Acute Lymphoblastic Leukemia\|Chronic Myeloid Leukemia\|Myelodysplastic Syndromes\|Myelofibrosis	Astex Pharmaceuticals	September 2006	Phase 1\|Phase 2

Tech Support

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.

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JAK Signaling Pathway Map

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AT9283