2. NF-κB Autophagy Apoptosis
  3. Keap1-Nrf2 p62 Ferroptosis
  4. Keap1-p-p62-IN-1

Keap1-p-p62-IN-1 is a potent and selective Keap1-p-p62 inhibitor with an IC50 of 0.11 μM. Keap1-p-p62-IN-1 shows 18.73-fold selectivity over Keap1-Nrf2 interaction. Keap1-p-p62-IN-1 normalizes Nrf2 ubiquitination, sensitizes cells to Sorafenib (HY-10201)-induced ferroptosis. Keap1-p-p62-IN-1 can be used for the research of p62 aberrant hepatocellular carcinoma.

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Keap1-p-p62-IN-1

Keap1-p-p62-IN-1 Chemical Structure

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Keap1-p-p62-IN-1 Related Antibodies

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Description

Keap1-p-p62-IN-1 is a potent and selective Keap1-p-p62 inhibitor with an IC50 of 0.11 μM. Keap1-p-p62-IN-1 shows 18.73-fold selectivity over Keap1-Nrf2 interaction. Keap1-p-p62-IN-1 normalizes Nrf2 ubiquitination, sensitizes cells to Sorafenib (HY-10201)-induced ferroptosis. Keap1-p-p62-IN-1 can be used for the research of p62 aberrant hepatocellular carcinoma[1].

In Vitro

Keap1-p-p62-IN-1 (compound 13) (0.625-5 μM; 48 h) induces ferroptosis in p62-aberrant Huh-1 HCC cells in a Keap1-dependent manner, as evidenced by concentration-dependent downregulation of ferroptosis-related proteins/genes, GSH depletion, iron overload, and increased lipid peroxidation (MDA, 4-HNE, Liperfluo)[1].
Keap1-p-p62-IN-1 (0.03-5 μM; 24-72 h) selectively disrupts Keap1-p-p62 PPI in a dose- and time-dependent manner, causing increased Nrf2 ubiquitination in HEK293T and Huh-1 cells[1].
Keap1-p-p62-IN-1 (0.625-5 μM; 24-72 h) specifically inhibits Nrf2 activity in tumor
cells (Huh-1; Huh-7; AML 12; A549) with p62-dependent overactivation of Nrf2[1].
Keap1-p-p62-IN-1 (1.25-10 μM; 48 h) induces ferroptosis in specific HCC cells[1].

Keap1-p-p62-IN-1 (1.25-10 μM; 14 days) dose-dependently inhibits colony formation in Huh-1 HCC cells[1].
Keap1-p-p62-IN-1 (1.25-10 μM; 24-72 h) selectively induces ferroptosis in Huh-1 HCC cells with p62-dependent overactivation of Nrf2[1].
Keap1-p-p62-IN-1 (2.5-10 μM; 24 h-14 days)sensitizes Huh-1 cells bearing p62-mediated Nrf2 hyper-activation to Sorafenib by cooperatively inducing ferroptosis[1].

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

Keap1-p-p62-IN-1 Related Antibodies

Western Blot Analysis[1]

Cell Line: HEK293T, Huh-1 cells
Concentration: 0.03; 0.1; 0.3 μM (HEK293T), 2.5; 5 μM (Huh-1 cells)
Incubation Time: 24; 36; 48; 72 h
Result: Effectively interfered with the Keap1−p-p62 interaction in a concentration-dependent manner without affecting the Keap1-Nrf2 interaction.
Barely disrupted the binding of both ETGE and DLGex motifs to Keap1.
Recovered the ability of Keap1 to interact with Nrf2 because of the elevated level of p62-free Keap1, leading to a decrease in the Nrf2 protein level of total cell lysate.
Elevated the accumulation of ubiquitinated Nrf2 upon MG132 (HY-13259) treatment.
Caused a time-dependent reduction in Nrf2 protein in both the nucleus and cytoplasm.
Showed a remarkable upregulation of the protein level of Keap1.

Real Time qPCR[1]

Cell Line: Huh-1 cells
Concentration: 2.5; 5 μM
Incubation Time: 24; 36; 48; 72 h
Result: Had no significant effect on the transcription level of NFE2L2 (encoding Nrf2 protein) in Huh-1 cells.
Concentration-dependently reduced mRNA levels of SLC7A11, FTL, and GPX4.

Western Blot Analysis[1]

Cell Line: Huh-1; Huh-7; AML 12; A549
Concentration: 0.625; 1.25; 2.5; 5 μM
Incubation Time: 24; 36; 48; 72 h
Result: Decreased the protein levels of Nrf2 and its downstream genes in a concentration- and time-dependent manner, including gluta-
mate-cysteine ligase catalytic subunit (GCLC), NAD(P)H dehydrogenase (quinone) 1 (NQO1), and heme oxygenase-1 (HO-1).
Downregulate the protein levels of these ferroptosis-related genes in a concentration-dependent manner.

Real Time qPCR[1]

Cell Line: Huh-1; Huh-7; AML 12; A549
Concentration: 0.625; 1.25; 2.5; 5 μM
Incubation Time: 24; 36; 48; 72 h
Result: Significantly downregulated the
mRNA levels of Nrf2-regulated genes GCLC, NQO1, and HO-1, with IC50 values of 4.62 μM, 4.24 μM, and 3.51 μM, respectively.
Induced a time-dependent decrease in the mRNA expression of GCLC, NQO1, and HO-1.

Cell Viability Assay[1]

Cell Line: Huh-1 HCC cells
Concentration: 1.25; 2.5; 5; 10 μM
Incubation Time: 48 h
Result: Decreased cell viability in a dose-dependent manner.
The growth inhibition induced by 13 in Huh-1 cells was mitigated by Fer-1 (5 μM).

Cell Proliferation Assay[1]

Cell Line: Huh-1 HCC cells
Concentration: 1.25; 2.5; 5; 10 μM
Incubation Time: 14 days
Result: Inhibited colony formation of Huh-1 HCC cells in a dose-dependent manner.
Parmacokinetics
Species Dose Route Cmax Tmax AUC0-∞ T1/2 Vz CL F
Rat[1] 5 mg/kg i.v. 5758.67 ng/mL 0.02 h 2111.50 ng·h/mL 2.82 h 10593.60 mL/kg 2825.97 mL/h/kg /
Rat[1] 25 mg/kg i.p. 2502.67 ng/mL 0.50 h 6022.41 3.08 h 19131.56 mL/kg 4279.65 mL/h/kg 57.04 %
In Vivo

Keap1-p-p62-IN-1 (compound 13) (20-40 mg/kg; i.p.; daily; 28 days) inhibits tumor growth in p62 aberrant Huh-1 xenograft mice, with reduced Nrf2 pathway activity and induction of ferroptosis-related changes in tumor tissue[1].

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

Animal Model: BALB/c nude mice (female) subcutaneously inoculated with Huh-1 cells[1]
Dosage: 20; 40 mg/kg
Administration: i.p.; daily; 28 days
Result: Achieved a tumor growth inhibition (TGI) rate of 11.1% at 20 mg/kg.
Achieved a TGI of 30.1% at 40 mg/kg.
Decreased protein levels of Nrf2, glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) in tumor tissues.
Reduced glutathione (GSH) levels in tumor tissues.
Increased ferrous iron (Fe2+) levels in tumor tissues.
Increased malondialdehyde (MDA) levels in tumor tissues.
Caused no significant body weight loss or histopathological lesions in major organs.
Molecular Weight

613.73

Formula

C33H35N5O5S
SMILES

CC1=CC(C)=C(S(N(C2=C(C=CC=C3)C3=C(OC(C4=CC=C(C(C)(C)C)C=C4)C(O)=O)C=C2)CC5=NN=NN5)(=O)=O)C(C)=C1
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Room temperature in continental US; may vary elsewhere.
Storage

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Purity & Documentation
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Keap1-p-p62-IN-1 Related Classifications

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  • 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:

Keap1-p-p62-IN-1Keap1-Nrf2p62FerroptosisSequestosome-1SQSTM1Keap1-p-p62ferroptosisGSHsorafenibiron overloadHuh-1 HCC cellslipid peroxidationubiquitinationp62 aberrant hepatocellular carcinoma cellsNrf2Inhibitorinhibitorinhibit

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