2. Apoptosis NF-κB Metabolic Enzyme/Protease Immunology/Inflammation MAPK/ERK Pathway
  3. Ferroptosis Necroptosis RIP kinase Reactive Oxygen Species (ROS) Mixed Lineage Kinase
  4. Zharp1-163

Zharp1-163 is a dual inhibitor of ferroptosis and necroptosis. Zharp1-163 effectively blocks ferroptosis by reducing reactive oxygen species (ROS) levels and inhibits necroptosis by potently and selectively targeting RIPK1 kinase activity (KD = 240 nM; IC50 = 406.1 nM). Zharp1-163 inhibits the cellular activation of RIPK1, RIPK3 and MLKL in response to necroptotic stimulation. Zharp1-163 markedly attenuates TNF-α (HY-P1875)-induced systemic inflammatory syndrome, including the prevention of TNF-α-induced mortality and hypothermia in mice. Zharp1-163 significantly alleviates acute kidney injury associated with both necroptosis and ferroptosis in models induced by Cisplatin (HY-17394) and ischemia-reperfusion. Zharp1-163 can be used for the study of diseases associated with cell death pathways, such as kidney disease.

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Zharp1-163

Zharp1-163 Chemical Structure

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Description

Zharp1-163 is a dual inhibitor of ferroptosis and necroptosis. Zharp1-163 effectively blocks ferroptosis by reducing reactive oxygen species (ROS) levels and inhibits necroptosis by potently and selectively targeting RIPK1 kinase activity (KD = 240 nM; IC50 = 406.1 nM). Zharp1-163 inhibits the cellular activation of RIPK1, RIPK3 and MLKL in response to necroptotic stimulation. Zharp1-163 markedly attenuates TNF-α (HY-P1875)-induced systemic inflammatory syndrome, including the prevention of TNF-α-induced mortality and hypothermia in mice. Zharp1-163 significantly alleviates acute kidney injury associated with both necroptosis and ferroptosis in models induced by Cisplatin (HY-17394) and ischemia-reperfusion. Zharp1-163 can be used for the study of diseases associated with cell death pathways, such as kidney disease[1].

In Vitro

Zharp1-163 (0.01-10μM, 18 h) significantly inhibits Erastin (HY-15763)-or RSL3 (HY-100218A)-induced ferroptosis in HT-1080 cells (EC50 = 0.95 μM; EC50 = 1.33 μM) and Mouse Embryonic Fibroblasts (MEFs) (EC50 = 1.93 μM; EC50 = 1.39 μM)[1].
Zharp1-163 (0.01-10 μM, 14-18 h) blocks TNF-α, Smac mimetic, and Z-VAD (HY-164388)-induced necroptosis in HT-29 cells (EC50 = 0.1 μM), and MEFs (EC50 = 0.11 μM)[1].
Zharp1-163 (0.01-10 μM, 14 h) efficiently inhibits TNFα and Z-VAD-induced necroptosis in mouse fibroblast L929 cells[1].
Zharp1-163 (0.3-3 μM, 26 h) inhibits apoptosis induced by TNFα plus Smac mimetic in MEFs[1].
Zharp1-163 (0.3-3 μM, 8 h) does not affect pyroptosis in THP-1 cells[1].
Zharp1-163 (10 μM, 7 h) significantly reduces lipid ROS production during ferroptosis and reduces the induction of both CHAC1 and PTGS2 induced by RSL3 in HT-1080 cells[1].
Zharp1-163 (0.1-3 μM, 10 h) eliminates the phosphorylation of RIPK1, RIPK3, and MLKL in human HT-29 cells and blocks the phosphorylation of RIPK1, RIPK3, and MLKL in MEFs[1].
Zharp1-163 (0.3-3 μM, 10 h) prevents both the generation of RIPK3 puncta and MLKL oligomerization in HT-29 cells[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Zharp1-163 Related Antibodies

Cell Viability Assay[1]

Cell Line: HT-1080 cells and MEFs.
Concentration: 0.01 μM, 0.1 μM, 1 μM, 10 μM
Incubation Time: Pretreated 2 h and then treated with Erastin or RSL3 for 16 h
Result: Significantly inhibited Erastin- or RSL3-induced ferroptosis in HT-1080 cells and MEFs.

Cell Viability Assay[1]

Cell Line: HT-1080 cells and MEFs.
Concentration: 0.01 μM, 0.1 μM, 1 μM
Incubation Time: Pretreated 2 h, followed by treatment with TNF-α (T) (40 ng/mL), Smac mimetic (S) (100 nM), Z-VAD (Z) (20 μM) for 12-16 h
Result: Blocked TNF-α, Smac mimetic, and Z-VAD-induced necroptosis in HT-29 cells (EC50 = 0.1 μM), in MEFs (EC50 = 0.11 μM).

Cell Viability Assay[1]

Cell Line: Mouse fibroblast L929 cells
Concentration: 0.01 μM, 0.1 μM, 1 μM
Incubation Time: 2 h, followed by treatment with T (40 ng/mL) and Z (20 μM) for 12 h
Result: Blocked TNF-α, Z-VAD-induced necroptosis in mouse fibroblast L929 cells (EC50 = 0.08 μM).

Apoptosis Analysis[1]

Cell Line: MEFs
Concentration: 0.3 μM, 1 μM, 3 μM
Incubation Time: 2 h before treatment with T (40 ng/mL) and S (100 nM) for 24 h
Result: Inhibited apoptosis induced by TNFα plus Smac mimetic in MEFs.

Real Time qPCR[1]

Cell Line: HT-1080 cells
Concentration: 10 μM
Incubation Time: 2 h, followed by induction with RSL3 for 5 h
Result: Significantly reduced the induction of both CHAC1 and PTGS2 in response to RSL3.

Western Blot Analysis[1]

Cell Line: HT-29 cells, MEFs
Concentration: 0.1 μM, 0.3 μM, 1 μM, 3 μM
Incubation Time: 2 h, followed by treatment with T (40 ng/mL), S (100 nM) and Z (20 μM) for 8 h
Result: Eliminated the phosphorylation of RIPK1, RIPK3, and MLKL in human HT-29 cells.
Blocked the phosphorylation of RIPK1, RIPK3, and MLKL in MEFs.

Immunofluorescence[1]

Cell Line: HT-29 cells stably expressing Flag-tagged RIPK3
Concentration: 0.3 μM, 1 μM, 3 μM
Incubation Time: Before the addition of T (40 ng/mL), S (100 nM), and Z (20 μM) for an additional 8 h, HT-29 cells stably expressing Flag-tagged RIPK3 were preincubated with the specified compounds for 2 h
Result: Prevented the generation of RIPK3 puncta.
In Vivo

Zharp1-163 (5 mg/kg, i.p., once) is a promising RIPK1 inhibitor, offers significant protection against TNF-induced SIRS in C57BL/6 mice[1]. Zharp1-163 (5 mg/kg, i.p., once) significantly alleviates acute kidney injury associated with both necroptosis and ferroptosis in models induced by Cisplatin and ischemia-reperfusion in C57BL/6 mice[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: C57BL/6 mice injected TNF[1].
Dosage: 5 mg/kg
Administration: I.p., pretreated with 30 min prior to challenge
Result: Significantly protected mice from TNF-α-induced lethality and reduced TNF-α-induced temperature loss in these mice.
Significantly ameliorated the production of proinflammatory cytokines, including IL-6.
Induced damage to the cecum and colon.
Animal Model: Cisplatin-induced acute kidney injury in C57BL/6 mice[1].
Dosage: 5 mg/kg
Administration: I.p., pretreated with 30 min prior to challenge
Result: Significantly inhibited cisplatin-induced body weight loss.
Mitigated mild inflammation and tubular epithelial cell damage.
Decreased the serum creatinine and blood urea nitrogen (BUN) levels in the context of Cisplatin-induced kidney injury.
Animal Model: The left renal artery of C57BL/6 mice pretreated for 2 h was isolated and clamped for 45 min via a nontraumatic artery clamp following right nephrectomy. Reperfusion was subsequently performed[1].
Dosage: 5 mg/kg
Administration: I.p., 2 h
Result: Significantly inhibited the levels of creatinine and BUN in mouse serum.
Molecular Weight

393.44

Formula

C21H23N5O3
SMILES

NC1=CN2C(C=CC(C3=CC4=C(N=C3)OCCN4C(OC5CCCCC5)=O)=C2)=N1
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Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
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Zharp1-163 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

Zharp1-163FerroptosisNecroptosisRIP kinaseReactive Oxygen Species (ROS)Mixed Lineage KinaseReceptor-interacting protein kinasesRIPKMLKsDual inhibitorRIPK1 kinaseInhibitorinhibitorinhibit

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