LY2784544

JAK2 inhibitor,highly potent and selective CAS# 1229236-86-5

LY2784544

Catalog No. BCC2200----Order now to get a substantial discount!

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Chemical structure

LY2784544

3D structure

Chemical Properties of LY2784544

Cas No. 1229236-86-5 SDF Download SDF
PubChem ID 46213929 Appearance Powder
Formula C23H25ClFN7O M.Wt 469.94
Type of Compound N/A Storage Desiccate at -20°C
Synonyms gandotinib
Solubility DMSO : ≥ 50 mg/mL (106.40 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 3-[(4-chloro-2-fluorophenyl)methyl]-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholin-4-ylmethyl)imidazo[1,2-b]pyridazin-6-amine
SMILES CC1=CC(=NN1)NC2=NN3C(=C(N=C3C(=C2)CN4CCOCC4)C)CC5=C(C=C(C=C5)Cl)F
Standard InChIKey SQSZANZGUXWJEA-UHFFFAOYSA-N
Standard InChI InChI=1S/C23H25ClFN7O/c1-14-9-21(29-28-14)27-22-11-17(13-31-5-7-33-8-6-31)23-26-15(2)20(32(23)30-22)10-16-3-4-18(24)12-19(16)25/h3-4,9,11-12H,5-8,10,13H2,1-2H3,(H2,27,28,29,30)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of LY2784544

DescriptionLY2784544 is a highly potent and selective inhibitor of wild-type JAK2 and V617F mutant JAK2 with IC50 values of 2.26 μM and 55 nM, respectively.
Targetswild-type JAK2V617F mutant JAK2    
IC502.26 μM55 nM    

Protocol

Cell Assay [1]
Ba/F3 cells expressing JAK2V617F are placed in RPMI-1640-containing vehicle (DMSO) or LY2784544 (concentration range, 0.001-20 μM) (1×104 cells/96-well). Ba/F3 cells expressing wild-type JAK2 are treated similarly except IL-3 (2 ng/mL) is added. After a 72-hour incubation, cell proliferation is assessed by adding Cell Titer 96 Aqueous One Solution Reagent (20 μL/well). The IC50 for inhibition of cell proliferation is calculated using the GraphPad Prism 4 software[1].

Animal Administration [1]
Mice[1]Dose- and time-dependent in vivo inhibition of JAK2V617F signaling is assessed by measuring inhibition of STAT5 phosphorylation in a mouse ascitic tumor model. Ba/F3-JAK2V617F-GFP cells (1×107) are implanted in the intraperitoneal cavity of severe combined immunodeficiency mice (SCID mice) and allowed to develop into ascitic tumors for 7 days. For dose-response studies (six animals/group), LY2784544 is administered once by oral gavage (2.5, 5, 10, 20, 40, or 80 mg/kg), then 30 min later, ascitic tumor cells are collected, fixed, incubated for 2 h with Mouse-anti-pSTAT5 (pY694) Alexa Fluor 647 (1:10 dilution), and analyzed by flow cytometry. Time course studies are performed similarly, except the animals are treated with LY2784544 at 20, 40 or 80 mg/kg and ascitic tumor cells collected at prespecified intervals of 0.25-6 h after dosing. Data are analyzed by the one-way analysis of variance, and Dunnett's test (α=0.05). Dose response data are analyzed with a four-parameter logistic curve-fitting program.

References:
[1]. Ma L, et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 2013, 3, e109.

LY2784544 Dilution Calculator

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Preparing Stock Solutions of LY2784544

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1279 mL 10.6397 mL 21.2793 mL 42.5586 mL 53.1983 mL
5 mM 0.4256 mL 2.1279 mL 4.2559 mL 8.5117 mL 10.6397 mL
10 mM 0.2128 mL 1.064 mL 2.1279 mL 4.2559 mL 5.3198 mL
50 mM 0.0426 mL 0.2128 mL 0.4256 mL 0.8512 mL 1.064 mL
100 mM 0.0213 mL 0.1064 mL 0.2128 mL 0.4256 mL 0.532 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on LY2784544

LY2784544 is a potent, selective inhibitor of JAK2 with IC50 value of 3 nM.[1]
Janus kinase 2 (JAK2) belongs to the Janus kinase family and is a member of the type II cytokine receptor family. It is a non-receptor tyrosine kinase. The JAK2 mutation (V617F) within the autoinhibitory pseudokinase domain results in a gain-of-function activation of JAK2.The JAK2V617F mutant results in subsequent phosphorylation of signal transducer and activator of transcription 5 (STAT5). Then, STAT5 regulates the transcription of genes associated with cell growth, death and differentiation. The JAK2V617F mutant is oncogenic in cells, and sufficient for generating the myeloproliferative neoplasms (MPN) phenotypes in murine models. Mutant JAK2 kinase is an attractive therapeutic target for the therapy of MPNs. To selectively inhibit JAK2V617F but minimizing inhibition of wild-type JAK2 would be an optimal treatment approach.
LY2784544 is a potent and ATP-competitive inhibitor of JAK2 tyrosine kinase. LY2784544 has 8- and 16-fold selectivity for JAK2 than JAK1 and JAK3, respectively. LY2784544 more effective on inhibiting the phosphorylation of STAT5 in Ba/F3-TEL-JAK2 cells than in Ba/F3-TEL- JAK3 and –JAK1 cells with IC 50 of 0.191 (JAK2), 2.904 (JAK1) and 4.744 nM (JAK3). LY2784544 significantly inhibited STAT5 phosphorylation at a concentration range from 50 nM–20 nM in Ba/F3 cells expressing JAK2V617F. On the other hand, LY2784544 showed minimal inhibition of STAT5 phosphorylation at 50 and 200 nM concentrations in IL-3-stimulated Ba/F3 cells which express wild-type JAK2. LY2784544 significantly inhibited the cell proliferation of JAK2V617F-expressing cells with IC50 =55 nM. In JAK2V617F-expressing cells, LY2784544 induced apoptosis with EC50±s.d.of 113±0.023 nM measured by Caspase3/7-glo assays.[1]
LY2784544 with a TED50 (threshold effective Dose 50) of 12.7 mg/kg, potently inhibits STAT5 phosphorylation in SCID mice bearing Ba/F3-JAK2V617F-GFP. In mouse hematologic disease model, LY2784544 also dose-dependly reduces Ba/F3-JAK2V617F-GFP tumor burden.[1]
References:
1.Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, Smith MC, Heinz-Taheny KM, Kreklau EL, Bloem L, Pitou C et al: Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J 2013, 3:e109.

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References on LY2784544

Photoredox catalysis in a complex pharmaceutical setting: toward the preparation of JAK2 inhibitor LY2784544.[Pubmed:25356724]

J Org Chem. 2014 Dec 5;79(23):11631-43.

We report a detailed investigation into the application of visible light-mediated photocatalysis to a challenging bond construction in a complex pharmaceutical target. The optimized reaction allowed the direct coupling of N-methylmorpholine with an unfunctionalized pyridazine in good yield and selectivity, and with high purity of the product isolated via crystallization. The reaction also facilitated the expedient synthesis of a range of analogues via the use of other commercially available N-methyl substituted tertiary amines, and therefore it represents an attractive tool for medicinal chemistry. Furthermore, a number of other interesting photoredox reactions were discovered during the course of this investigation, such as a formal methylation reaction via C-N bond cleavage, functionalization of C-H bonds alpha to amides, and a visible light-mediated iminium ion reduction.

Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F.[Pubmed:23584399]

Blood Cancer J. 2013 Apr 12;3:e109.

Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.

Description

Gandotinib (LY2784544) is a potent JAK2 inhibitor with IC50 of 3 nM. Gandotinib (LY2784544) also inhibits FLT3, FLT4, FGFR2, TYK2, and TRKB with IC50 of 4, 25, 32, 44, and 95 nM.

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