2. NF-κB PI3K/Akt/mTOR Epigenetics MAPK/ERK Pathway Immunology/Inflammation Neuronal Signaling
  3. Keap1-Nrf2 AMPK JNK IKK p38 MAPK NO Synthase α-synuclein Interleukin Related
  4. KMS99220

KMS99220 is an orally active, blood-brain barrier-permeable activator of the Nrf2 inhibitory protein Keap-1. KMS99220 enhances the activity of AMPK, activates the Nrf2 signaling pathway, and reduces the phosphorylation of IκB, nuclear translocation of NFκB, as well as the phosphorylation levels of JNK, IKK and p38 MAPK via HO-1. KMS99220 binds to Keap1 to trigger the nuclear translocation of Nrf2, induces the expression of HO-1, NQO1, GCLC, GCLM and proteasome subunits; enhances proteasomal enzymatic activity; inhibits iNOS expression, nitric oxide production and IL-1β generation; attenuates microglial activation; reduces α-synuclein aggregation; and prevents dopaminergic neuron degeneration and motor dysfunction. KMS99220 prevents the degeneration of dopaminergic neurons in the substantia nigra, induces the expression of Nrf2 downstream target genes, and effectively ameliorates associated motor dysfunction in a mouse model of Parkinson's disease. KMS99220 is applicable to research related to Parkinson's disease.

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KMS99220

KMS99220 Chemical Structure

CAS No. : 1478585-60-2

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Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO
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Based on 1 publication(s) in Google Scholar

KMS99220 Related Antibodies

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NUAK1 NUAK2 AMPK AMPK α1β1γ1 AMPK α2β1γ1 AMPK α1β2γ1 AMPK α2β2γ1 BRSK1 BRSK2 HUNK AMPKα

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IKK-α IKK-β IKK IKKε TBK1

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p38 MAPK Akt1 p38α p38β MAPK13 p38δ p38γ

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nNOS iNOS eNOS

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α-synuclein α-synuclein Aggregation α-synuclein/CHMP2B

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IL-1 IL-2 IL-3 IL-4 IL-5 IL-6 IL-8 IL-10 IL-12 IL-13 IL-15 IL-17 IL-23 IL-7 IL-33 IL-22 IL-18

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Description

KMS99220 is an orally active, blood-brain barrier-permeable activator of the Nrf2 inhibitory protein Keap-1. KMS99220 enhances the activity of AMPK, activates the Nrf2 signaling pathway, and reduces the phosphorylation of IκB, nuclear translocation of NFκB, as well as the phosphorylation levels of JNK, IKK and p38 MAPK via HO-1. KMS99220 binds to Keap1 to trigger the nuclear translocation of Nrf2, induces the expression of HO-1, NQO1, GCLC, GCLM and proteasome subunits; enhances proteasomal enzymatic activity; inhibits iNOS expression, nitric oxide production and IL-1β generation; attenuates microglial activation; reduces α-synuclein aggregation; and prevents dopaminergic neuron degeneration and motor dysfunction. KMS99220 prevents the degeneration of dopaminergic neurons in the substantia nigra, induces the expression of Nrf2 downstream target genes, and effectively ameliorates associated motor dysfunction in a mouse model of Parkinson's disease. KMS99220 is applicable to research related to Parkinson's disease[1][2][3].

Cellular Effect
Cell Line Type Value Description References
U2OS EC50
1.36 μM
Compound: 6a
Activation of NRF2 in human U2OS cells co-expressing Keap1 (unknown origin) assessed as induction of NRF2 translocation to nucleus incubated for 6 hrs by beta-galactosidase based chemiluminescent assay
Activation of NRF2 in human U2OS cells co-expressing Keap1 (unknown origin) assessed as induction of NRF2 translocation to nucleus incubated for 6 hrs by beta-galactosidase based chemiluminescent assay
[PMID: 31670201]
In Vitro

KMS99220 (5-10 μM; 40 min) directly activates purified AMPK protein, increasing its enzymatic activity by 17% at a concentration of 10 μM[1].
KMS99220 (1-10 μM; 15 min) dose-dependently enhances the phosphorylation level of AMPK in BV2 cells[1].
KMS99220 (6-24 h, 0.5-10 μM) dose-dependently induces HO-1 mRNA and protein expression in BV2 mouse microglia[1].
KMS99220 (10 μM; 1 h) inhibits LPS (HY-D1056)-induced nuclear translocation of NF-κB (p65), suppresses IκB phosphorylation, and maintains the total IκB protein level in BV2 mouse microglial cells[1].
KMS99220 (6 h for iNOS mRNA detection, 24 h for iNOS protein and nitrite detection; 0.5-10 μM) inhibits LPS-induced iNOS expression and nitric oxide production in BV2 mouse microglia in a dose-dependent manner, and completely suppresses NO production at a concentration of 10 μM[1].
KMS99220 (pre-incubated at 10 μM for 1 h) exerts Nrf2-independent early anti-inflammatory effects in BV2 mouse microglia, including induction of HO-1 expression in Nrf2-knockdown cells, inhibition of LPS-induced IκB phosphorylation, and suppression of LPS-induced iNOS expression[1].
KMS99220 (5-100 μM) binds to purified Keap1 protein with high affinity, with a Kd value of 2.2 × 10-8 M[2].
KMS99220 (3-24 h, 0.5-3 μM) promotes nuclear translocation of Nrf2 (reaching 2.6-fold after treatment with 3 μM for 3 h) and total Nrf2 expression (reaching 1.9-fold after treatment with 3 μM for 24 h) in CATH.a dopaminergic cells without inducing cytotoxicity[2].
KMS99220 (0.5-3 μM; 6 h-24 h) dose-dependently induces the mRNA and protein expression of Nrf2-dependent antioxidant enzymes (NQO1, HO-1, GCLC, GCLM) in CATH.a dopaminergic cells, with the effect peaking at 3 μM[2].
KMS99220 (0.5-3 μM; 16-24 h) dose-dependently upregulates the mRNA and protein expression levels of proteasome subunits (PSMB5, PSMB8, PSMA1, PSMB7) in CATH.a dopaminergic cells, and enhances their chymotrypsin-like, trypsin-like and caspase-like proteasome activities, with the peak effect observed at 3 μM[2].
KMS99220 (24 h, 3 μM) reduces the level of aggregated α-synuclein in CATH.a dopaminergic cells transfected with GFP-α-syn A53T[2].
KMS99220 (0.5-10 μM; 6-24 h) inhibits LPS-induced production of IL-1β mRNA and protein in BV-2 microglia[3].
KMS99220 (1.5 h, 0.5-10 μM) inhibits LPS-induced phosphorylation of IKK, JNK, p38 MAPK and ERK in BV-2 microglia via HO-1 mediation, with the strongest inhibitory effect observed at the concentration of 10 μM[3].
KMS99220 (0.5-10 μM; 3-24 h) activates the Nrf2 pathway in BV-2 microglial cells with or without LPS stimulation by promoting the nuclear translocation of Nrf2, and induces the expression of Nrf2 target genes (HO-1, NQO1, GCLC, GCLM) and their corresponding proteins in a dose-dependent manner[3].

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

KMS99220 Related Antibodies

Western Blot Analysis[1]

Cell Line: BV2 cells
Concentration: 0, 1, 5, 10 μM (15 min incubation); 10 μM (15, 30, 60, 180 min incubation)
Incubation Time: 15 min (dose-dependent analysis); 15, 30, 60, 180 min (time-course analysis)
Result: Induced p-AMPK levels in a dose-dependent manner: 2.6-fold at 1 μM, 3.4-fold at 5 μM, 5.1-fold at 10 μM relative to untreated control after 15 min incubation.
Reached peak p-AMPK levels of 2.3-fold relative to control at 15 min with 10 μM treatment, then decreased over time.
Caused nuclear accumulation of p-AMPK between 15 and 60 min with 10 μM treatment.

RT-PCR[1]

Cell Line: BV2 cells
Concentration: 0, 0.5, 1, 5, 10 μM
Incubation Time: 6 h
Result: Dramatically and dose-dependently elevated the mRNA
levels of HO-1.

Western Blot Analysis[1]

Cell Line: LPS-challenged BV2 mouse microglial cells
Concentration: 10 μM (pre-incubation)
Incubation Time: 1 h pre-incubation prior to 1 h LPS challenge
Result: Reduced LPS-induced nuclear NFκB (p65) levels to 0.5-fold relative to LPS-treated control.

Western Blot Analysis[1]

Cell Line: LPS-challenged BV2 mouse microglial cells
Concentration: 10 μM (pre-incubation)
Incubation Time: 1 h pre-incubation prior to 0.5 h LPS challenge
Result: Reduced LPS-induced p-IκB levels to 0.7-fold relative to LPS-treated control.
Prevented the LPS-induced decrease in total IκB protein levels, maintaining IκB at 2.5-fold relative to LPS-treated control.
Parmacokinetics
Species Dose Route Cmax AUCall F CL Vz T1/2
Mice[2] 5 mg/kg i.v. / 165.3 ng·h / 30.2 L/h/kg 58.9 L/kg 1.4 h
Mice[2] 30 mg/kg p.o. 224.4 ng/mL 718.7 ng·h 72.5 % / / /
In Vivo

KMS99220 (10-30 mg/kg; p.o.; once every 24 hours; for 3 consecutive days) prevents MPTP (HY-15608)-induced nigrostriatal dopaminergic neuron degeneration, activates Nrf2 target genes, completely reverses associated motor deficits in male C57BL/6 mice, fully abrogates MPTP-induced microglial activation in mice, reduces iNOS levels, and normalizes IL-1β levels[2].

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

Animal Model: C57BL/6 (male, 23-25 g, MPTP-induced Parkinson's disease model)[2]
Dosage: 10 mg/kg; 30 mg/kg
Administration: p.o.; every 24 h; 3 consecutive days
Result: Attenuated loss of tyrosine hydroxylase (TH)-immunopositive nigral dopaminergic neurons to 78% of vehicle-treated control at 10 mg/kg.
Attenuated loss of TH-immunopositive striatal fibers to 76% of vehicle-treated control at 10 mg/kg.
Reversed MPTP-induced hindlimb movement deficits at 10 mg/kg.
Restored rotarod latency to 289 seconds at 10 mg/kg.
Normalized vertical grid test parameters to near vehicle-control levels at 10 mg/kg.
Attenuated loss of TH-immunopositive nigral dopaminergic neurons to 84% of vehicle-treated control at 30 mg/kg.
Fully preserved TH-immunopositive striatal fibers to 98% of vehicle-treated control at 30 mg/kg.
Reversed MPTP-induced hindlimb movement deficits at 30 mg/kg.
Restored rotarod latency to 292 seconds at 30 mg/kg.
Normalized vertical grid test parameters to near vehicle-control levels at 30 mg/kg.
Increased striatal protein levels of Nrf2 to 4.0-fold of vehicle-treated control, NQO1 to 1.4-fold, HO-1 to 2.2-fold, GCLM to 4.0-fold, and GCLC to 1.6-fold at 30 mg/kg.
Increased HO-1 (2.3-fold) and GCLM (7.0-fold) staining in surviving TH-positive nigral dopaminergic neurons at 30 mg/kg.
Completely abrogated MPTP-induced increases in Iba-1 immunoreactivity (microglial activation) to levels not significantly different from vehicle-treated controls at both 10 mg/kg and 30 mg/kg doses.
Suppressed MPTP-induced increases in striatal inducible nitric oxide synthase (iNOS) protein levels by 70% at 30 mg/kg dose.
Completely nullified MPTP-induced increases in nigral interleukin 1 beta (IL-1β) levels, returning IL-1β to levels not significantly different from vehicle-treated controls at 30 mg/kg dose.
Molecular Weight

455.90

Formula

C23H25ClF3NO3
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

O=C(C1=CC=C(C=C1)OCCCN2CCOCC2)/C=C/C3=C(C=CC=C3)C(F)(F)F.Cl
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

4°C, sealed storage, away from moisture

*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

Solvent & Solubility
In Vitro: 

DMSO : 100 mg/mL (219.35 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 2.1935 mL 10.9673 mL 21.9346 mL
5 mM 0.4387 mL 2.1935 mL 4.3869 mL
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

  • Molarity Calculator

  • Dilution Calculator

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass
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Molecular Weight *

Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

This equation is commonly abbreviated as: C1V1 = C2V2

Concentration (start)

C1

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C2

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Volume (final)

V2

In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

  • Protocol 1

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

    Solubility: ≥ 5 mg/mL (10.97 mM); Clear solution

    This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

    Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
  • Protocol 2

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

    Solubility: ≥ 5 mg/mL (10.97 mM); Clear solution

    This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

    Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

Dosage

mg/kg

Animal weight
(per animal)

g

Dosing volume
(per animal)

μL

Number of animals

Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
%
DMSO +
% 
+
%
Tween-80 +
%
Saline
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration: mg/mL
Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).

*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 2.1935 mL 10.9673 mL 21.9346 mL 54.8366 mL
5 mM 0.4387 mL 2.1935 mL 4.3869 mL 10.9673 mL
10 mM 0.2193 mL 1.0967 mL 2.1935 mL 5.4837 mL
15 mM 0.1462 mL 0.7312 mL 1.4623 mL 3.6558 mL
20 mM 0.1097 mL 0.5484 mL 1.0967 mL 2.7418 mL
25 mM 0.0877 mL 0.4387 mL 0.8774 mL 2.1935 mL
30 mM 0.0731 mL 0.3656 mL 0.7312 mL 1.8279 mL
40 mM 0.0548 mL 0.2742 mL 0.5484 mL 1.3709 mL
50 mM 0.0439 mL 0.2193 mL 0.4387 mL 1.0967 mL
60 mM 0.0366 mL 0.1828 mL 0.3656 mL 0.9139 mL
80 mM 0.0274 mL 0.1371 mL 0.2742 mL 0.6855 mL
100 mM 0.0219 mL 0.1097 mL 0.2193 mL 0.5484 mL
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KMS99220 Related Classifications

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:

KMS992201478585-60-2KMS 99220KMS-99220Keap1-Nrf2AMPKJNKIKKp38 MAPKNO Synthaseα-synucleinInterleukin RelatedAMP-activated protein kinasec-Jun N-terminal kinaseIκB kinaseI kappa B kinase Nitric oxide synthasesNOSα-SynILNrf2 inhibitory protein Keap-1 ActivatorCATH.a dopaminergic cellsBV2 cellsC57BL/6 miceParkinson's diseaseInhibitorinhibitorinhibit

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