Name: GSK-872
Brand: GlpBio
SKU: GC19175
Availability: InStock
Rating: 5 (27 reviews)

Product has been cited by 4 publications

Product Documents

Quality Control & SDS

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Purity: >99.50%

Protocol

Cell experiment [1]:
Cell lines	HT-29 cells
Preparation Method	Relative viability of human HT-29 cells 24 hr posttreatment (hpt) with TNF (10 ng/ml), zVAD-fmk (zVAD; 20 μM), and SMAC007 (100 nM) in the presence of increasing concentrations of GSK-872, assessed by determining ATP levels (mean ± range is shown) compared to cells treated with vehicle (DMSO) alone.
Reaction Conditions	0.01, 0.03 , 0.1, 0.3, 1, and 3 μM；24 hours
Applications	When evaluated in cell culture using human HT-29 cells,GSK-872 ( 0.01-3 μM; 24 hours) blocks TNF-induced necroptosis in human HT-29 cells in a concentration-dependent manne^[1].
Animal experiment [2]:
Animal models	Sprague-Dawley male rats with 300–320 g body weight
Preparation Method	GSK-872 was diluted with 1% DMSO to a concentration of 25 mM, and 6 μL of GSK-872 or diluted DMSO was administrated by a syringe pump at 30 min after SAH as previously described, Neurological function (n = 24) was evaluated at 24 h and 72 h after operation. Brain edema (n = 6), western blot (n = 6), PI staining (n = 6) and HMGB1 immunofluorescence (n = 6) were evaluated at 72 h after SAH.
Dosage form	6ul 25mM; 24 h and 72 h
Applications	GSK-872 hydrochloride (25 mM; intracerebroventricular injection) can attenuate brain edema and improve neurological function following subarachnoid hemorrhage (SAH) and reduce the number of necrotic cells. GSK-872 hydrochloride can also decrease the protein levels of RIPK3 and MLKL, and cytoplasmic translocation and expression of HMGB1, an important pro-inflammatory protein^[2].
References: [1]. Mandal P, Berger SB, et, al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 2014 Nov 20;56(4):481-95. doi: 10.1016/j.molcel.2014.10.021. Epub 2014 Nov 20. PMID: 25459880; PMCID: PMC4512186. [2]. Chen T, Pan H, et, al. Inhibiting of RIPK3 attenuates early brain injury following subarachnoid hemorrhage: Possibly through alleviating necroptosis. Biomed Pharmacother. 2018 Nov;107:563-570. doi: 10.1016/j.biopha.2018.08.056. Epub 2018 Aug 14. PMID: 30114640.

GSK-872 is a RIPK3 inhibitor. GSK-872 decreases the RIPK3-mediated necroptosis and subsequent cytoplasmic translocation and expression of HMGB1, as well as ameliorates brain edema and neurological deficits in early brain injury^[5]. GSK-872 bound RIP3 kinase domain with high affinity (IC₅₀ = 1.8 nM) and inhibited kinase activity (IC₅₀ = 1.3 nM) ^[1]. GSK-872 prevented virus-induced necrosis, a pathway dependent on DAI-RIP3 complex formation,GSK-872 blocked TLR3-induced necrosis induced in fibroblasts by poly(I:C) in the presence of Z-VAD-fmk, Both virus- and TLR3-induced necrosis proceed independently of RIP1 kinase inhibition by Nec-1 but sensitive to inhibition by GSK-872 ^[2,3,4]. Pharmacological inhibitor GSK-872 enhanced insulin signaling in vitro and in vivo, which contributing to improve insulin sensitivity^[9].

When evaluated in cell culture using human HT-29 cells, GSK-872 bind the kinase domain and inhibit kinase activity with high specificity, targeting a broader range of pronecrotic stimuli ^[1]. RIP3i compounds GSK-872 blocked TNF-induced necroptosis in a concentration-dependent manner . In cell-based assays, there was a 100- to 1,000-fold shift in the IC₅₀ compared to the cell-free biochemical assays. GSK-872 blocked necroptosis in primary human neutrophils isolated from whole blood，and blocked necroptosis in mouse cells. Mouse bone-marrow-derived macrophages (BMDMs) or thioglycolate-elicited peritoneal macrophages (PECs), as well as 3T3SA fibroblasts, were also protected by GSK-872 concentrations .

GSK-872 significantly reduced brain edema and improved neurological function in SAH rats, and reduced the number of necrotic cells. The exact mechanism of GSK-872 induced neuroprotective effect against SAH was identified^[6,7].Inhibiting of RIPK3 by GSK-872 could attenuate RIPK3-dependent necroptosis, decrease brain edema, and improve neurological function after SAH. GSK-872 also improves hepatic steatosis and liver injury in mice fed with HFCD after CIH exposure^[8].

References:
[1]: Mandal P, Berger SB, et, al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 2014 Nov 20;56(4):481-95. doi: 10.1016/j.molcel.2014.10.021. Epub 2014 Nov 20. PMID: 25459880; PMCID: PMC4512186.
[2]:Kaiser WJ, Sridharan H, et, al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem. 2013 Oct 25;288(43):31268-79. doi: 10.1074/jbc.M113.462341. Epub 2013 Sep 9. PMID: 24019532; PMCID: PMC3829437.
[3]: Arora D, Siddiqui MH, et, al. Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes. Biochem Biophys Res Commun. 2016 Oct 14;479(2):217-223. doi:
[4]: He S, Liang Y, Shao F, Wang X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20054-9. doi: 10.1073/pnas.1116302108. Epub 2011 Nov 28. PMID: 22123964; PMCID: PMC3250173.
[5]: Chen T, Pan H, et, al. Inhibiting of RIPK3 attenuates early brain injury following subarachnoid hemorrhage: Possibly through alleviating necroptosis. Biomed Pharmacother. 2018 Nov;107:563-570. doi: 10.1016/j.biopha.2018.08.056. Epub 2018 Aug 14. PMID: 30114640.
[6]: Chen S, Lv X, et, al.RIPK1/RIPK3/MLKL-mediated necroptosis contributes to compression-induced rat nucleus pulposus cells death. Apoptosis. 2017 May;22(5):626-638. doi: 10.1007/s10495-017-1358-2. PMID: 28289909.
[7]: Liu T, Zhao DX, et, al. Therapeutic hypothermia attenuates tissue damage and cytokine expression after traumatic brain injury by inhibiting necroptosis in the rat. Sci Rep. 2016 Apr 15;6:24547. doi: 10.1038/srep24547. PMID: 27080932; PMCID: PMC4832230.
[8]: Zhang H, Zhou L, Z et, al. Intermittent hypoxia aggravates non-alcoholic fatty liver disease via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway. Life Sci. 2021 Nov 15;285:119963. doi: 10.1016/j.lfs.2021.119963. Epub 2021 Sep 16. PMID: 34536498.
[9]:Xu H, Du X, et, al. The pseudokinase MLKL regulates hepatic insulin sensitivity independently of inflammation. Mol Metab. 2019 May;23:14-23. doi: 10.1016/j.molmet.2019.02.003. Epub 2019 Feb 20. PMID: 30837196; PMCID: PMC6480316.

Cas No.	1346546-69-7	SDF
Canonical SMILES	O=S(C1=CC=C2N=CC=C(NC3=CC=C(SC=N4)C4=C3)C2=C1)(C(C)C)=O
Formula	C₁₉H₁₇N₃O₂S₂	M.Wt	383.49
Solubility	DMSO : ≥ 100 mg/mL (260.76 mM)	Storage	Store at -20°C
General tips	Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition	Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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		1 mg	5 mg	10 mg
	1 mM	2.6076 mL	13.0381 mL	26.0763 mL
	5 mM	0.5215 mL	2.6076 mL	5.2153 mL
	10 mM	0.2608 mL	1.3038 mL	2.6076 mL

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