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Chemical Structure| 579515-63-2 Chemical Structure| 579515-63-2

Structure of GW806742X
CAS No.: 579515-63-2

Chemical Structure| 579515-63-2

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GW806742X, an ATP analog, is a potent MLKL inhibitor that binds to the MLKL pseudokinase domain with a Kd value of 9.3μM. GW806742X has anti-VEGFR2 activity (IC50=2 nM). GW806742X delays MLKL membrane displacement and inhibits necrosis.

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Product Details of GW806742X

CAS No. :579515-63-2
Formula : C25H22F3N7O4S
M.W : 573.55
SMILES Code : O=C(NC1=CC=C(OC(F)(F)F)C=C1)NC2=CC=C(C=C2)N(C)C3=NC(NC4=CC(S(=O)(N)=O)=CC=C4)=NC=C3
MDL No. :MFCD29036385
InChI Key :SNRUTMWCDZHKKM-UHFFFAOYSA-N
Pubchem ID :5329829

Safety of GW806742X

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Related Pathways of GW806742X

RTK
MAPK

Isoform Comparison

Biological Activity

Target
  • MLKL

    MLKL, Kd:9.3 μM

In Vitro:

Cell Line
Concentration Treated Time Description References
MEF cells 1 µM 1 hour GW806742X, as an MLKL inhibitor, was used to study its role in complement-dependent cytotoxicity. Results showed that GW806742X failed to inhibit CDC in Bid KO MEFs. Front Immunol. 2018 Feb 23;9:306
murine bone marrow-derived macrophages 1 μM 6 hours inhibited MSU crystal-induced necrosis Acta Pharmacol Sin. 2022 May;43(5):1324-1336
K-562 leukemia cells 1 µM 72 hours GW806742X significantly reduced AURKA and AURKB expression and induced apoptosis and G2/M phase cell cycle arrest. Sci Rep. 2020 Dec 4;10(1):21272
RAW264.7 cells 2 μM 6 hours GW806742X significantly reduced LDH release and the proportion of necrotic cells in E. faecalis-infected RAW264.7 cells and decreased the expression of inflammatory cytokines. Microbiol Spectr. 2022 Aug 31;10(4):e0104522
U937 monocytes 1 µM 24 hours In high glucose conditions, GW806742X, as an MLKL inhibitor, prevented cell death. Int J Mol Sci. 2023 May 11;24(10):8609
AsPC-1 cells 1 µM 48 hours Inhibited MLKL-driven necroptosis, reduced levels of necroptosis markers p-MLKL and MLKL oligomers Nat Commun. 2024 Jul 18;15(1):6043
PANC-1 cells 1 µM 48 hours Inhibited MLKL-driven necroptosis, reversed growth arrest and increased necroptosis level (p-MLKL level) in T1M1 PDOs Nat Commun. 2024 Jul 18;15(1):6043
SW620 cells 1 μM 1.5 hours To evaluate the inhibitory effect of GW806742X on EBI-induced necroptosis in SW620 cells Front Pharmacol. 2023 Jun 16;14:1219362

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
C57BL/6 mice Orthotopic xenograft model and liver metastasis model Intravenous injection 100 µM in 50 µl 3 times per week for 4 weeks GW treatment reduced the incidence of liver metastasis without affecting primary tumor lesions, and the combination regimen with anti-CD47 showed the best tumor control and survival improvement Nat Commun. 2024 Jul 18;15(1):6043
Mice S. marcescens pneumonia model Intraperitoneal injection 100 μl of 100 μM Every 4h for the first 12h post-infection Reduced bacterial burden in the lungs and protection of alveolar macrophages PLoS Pathog. 2015 Dec 11;11(12):e1005337

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

1.74mL

0.35mL

0.17mL

8.72mL

1.74mL

0.87mL

17.44mL

3.49mL

1.74mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2

References

[1]Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, Pierotti C, Garnier JM, Dobson RC, Webb AI, Tripaydonis A, Babon JJ, Mulcair MD, Scanlon MJ, Alexander WS, Wilks AF, Czabotar PE, Lessene G, Murphy JM, Silke J. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7. doi: 10.1073/pnas.1408987111. Epub 2014 Oct 6. PMID: 25288762; PMCID: PMC4210347.

[2]Sammond DM, Nailor KE, Veal JM, Nolte RT, Wang L, Knick VB, Rudolph SK, Truesdale AT, Nartey EN, Stafford JA, Kumar R, Cheung M. Discovery of a novel and potent series of dianilinopyrimidineurea and urea isostere inhibitors of VEGFR2 tyrosine kinase. Bioorg Med Chem Lett. 2005 Aug 1;15(15):3519-23. doi: 10.1016/j.bmcl.2005.05.096. PMID: 15990302.

[3] Andre L Samson,et al. MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis. Nat Commun. 2020 Jun 19;11(1):3151.

[4]Jialin Dai,et al. A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression. Cell Death Dis. 2020 Apr 24;11(4):282.

[5] Bingqing Xia,et al. MLKL forms cation channels. Cell Res. 2016 May;26(5):517-28.

[6]Sevda Lule,et al. Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab. 2021 Jul;41(7):1623-1633.

[7]Kimberley D Gutierrez,et al. MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D. J Immunol. 2017 Mar 1;198(5):2156-2164.

[8] Hildebrand JM, et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7.

 

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