LMP2-IN-1
LMP2-IN-1 is an orally bioavailable, brain-permeable macrocyclic peptide epoxyketone, acts as a selective and irreversible inhibitor of LMP2 (IC50 = 87 nM). LMP2-IN-1 rapidly distributes to the brain and forms an irreversible LMP2:AR-01 adduct. LMP2-IN-1 improves memory function and rescues reactive astrocytes in 5xFAD mouse models of Alzheimer's disease (AD).
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- No. CAS: 3056058-96-6
- Fòrmula: C23H36FN3O6
- Peso molecular:469.55
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Actividad biológica
Descripciòn
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| ARPE-19 | IC50 |
100 μM
Compound: 5
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Cytotoxicity against human ARPE-19 cells assessed as reduction in cell viability incubated for 96 hrs by CellTiter 96 Aqueous One Solution Cell Proliferation Assay
Cytotoxicity against human ARPE-19 cells assessed as reduction in cell viability incubated for 96 hrs by CellTiter 96 Aqueous One Solution Cell Proliferation Assay
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[PMID: 38636481] |
In Vitro
LMP2-IN-1 (compound AR-01) (0-500 nM; 24 h) dose-dependently inhibits LMP2 activity and forms LMP2:AR-01 adduct in murine microglial BV2 cells[1].
LMP2-IN-1 (compound 5) inhibits human 20S immunoproteasome LMP2 activity with an IC50 of 87 nM[2].
LMP2-IN-1 (10 μM; 120 min) shows high Caco2 cell permeability with an apparent permeability of 23.4 × 10^-6 cm/s and a low efflux ratio (ER) of 0.4[2].
LMP2-IN-1 (0.01-100 μM; 96 h) shows no cytotoxicity in normal human HMC3 microglia cells and ARPE19 retinal pigment epithelial cells up to 30 μM and 100 μM, respectively[2].
LMP2-IN-1 (1 mg/mL, 4-fold serial dilution) is negative in the AMES test using S. typhimurium TA98 and TA100 strains with or without S9 fraction[2].
LMP2-IN-1 (2 μM; 4 h) exhibits a human plasma protein unbound fraction (fu) of 0.45 ± 0.07 as determined by equilibrium dialysis[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:BV2 cells
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Concentration:0-500 nM
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Incubation Time:24 h
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Result:Inhibited LMP2 activity and formed LMP2:AR-01 adduct in a dose-dependent manner.
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Cell Line:BV2 cells
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Concentration:0-500 nM
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Incubation Time:24 h
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Result:Inhibited LMP2 activity and formed LMP2:AR-01 adduct in a dose-dependent manner.
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Cell Line:human HMC3 microglia cells and ARPE19 retinal pigment epithelial cells
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Concentration:0.01-100 μM
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Incubation Time:96 h
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Result:Showed no cytotoxicity in normal human HMC3 microglia cells and ARPE19 retinal pigment epithelial cells up to 30 μM and 100 μM, respectively.
Parmacokinetics
| Species | Dose | Route | Note | AUC0-last | AUCinf | Brain-Kp | C0 | Cmax | CL | F | T1/2 | Tmax | Vss |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 150 mg/kg | i.p. | plasma | 11000 ng/mL·h | NA ng/mL·h | NA | NA ng/mL | 29800 ng/mL | NA mL/h/kg | 53.8 % | 0.162 h | 0.25 h | NA mL/kg |
| Mice[2] | 150 mg/kg | p.o. | / | 3553 ng/mL·h | 3571 ng/mL·h | / | NA ng/mL | 3630 ng/mL | NA mL/h/kg | 9.8 % | 0.791 h | 0.333 h | NA mL/kg |
| Mice[2] | 40 mg/kg | i.v. | / | 9689 ng/mL·h | 9689 ng/mL·h | / | 31987 ng/mL | 25900 ng/mL | 4253 mL/h/kg | NA % | 0.420 h | 0.083 h | 2572 mL/kg |
| Mice[1] | 80 mg/kg | i.v. | plasma | 10900 ng/mL·h | 10900 ng/mL·h | NA | 94900 ng/mL | 41200 ng/mL | 7310 mL/h/kg | NA % | 0.710 h | 0.083 h | 7490 mL/kg |
| Mice[1] | 80 mg/kg | i.v. | brain | 185 ng/mL·h | 185 ng/mL·h | 0.0170 | NA ng/mL | 680 ng/mL | NA mL/h/kg | NA % | 0.137 h | 0.083 h | NA mL/kg |
| Rat[1] | 40 mg/kg | i.v. | plasma | 11500 ng/mL·h | 12150 ng/mL·h | NA | 67700 ng/mL | 52500 ng/mL | 3420 mL/h/kg | NA % | 0.459 h | 0.033 h | 2270 mL/kg |
In Vivo
LMP2-IN-1 (150 mg/kg; i.p.; single dose) achieves approximately 54% bioavailability and complete LMP2:AR-01 adduct formation in the mouse brain at 6 h postdose in healthy BALB/c mice (male, 7 weeks old)[1].
LMP2-IN-1 (150 mg/kg; p.o.; single dose) achieves approximately 10% oral bioavailability and approximately 71% LMP2:AR-01 adduct formation in the mouse brain in healthy BALB/c mice (male, 7 weeks old)[1].
LMP2-IN-1 (20 mg/kg; i.p.; twice weekly for 3 weeks) achieves cumulative brain LMP2 occupancy (approximately 46% adduct formation at day 21) in aged C57BL/6 mice (female, 8 months old)[1].
LMP2-IN-1 (20 mg/kg; i.p.; twice weekly for 3 weeks) improves spatial memory performance and rescues reactive astrocytes in 5xFAD mice (4 months old, both sexes)[1].
LMP2-IN-1 (compound 5) (150 mg/kg; p.o.; single dose) inhibits approximately 90% of blood LMP2 activity and 21% of brain LMP2 activity at 6 h postdose in healthy BALB/c mice (male, 7 weeks old)[2].
LMP2-IN-1 (40 mg/kg; i.v.; single dose) is detected in brain, liver, kidney, and spleen at 2 h postdose, but not detected in lung tissues in healthy BALB/c mice (male, 7 weeks old)[2].
LMP2-IN-1 (5-100 mg/kg; i.v.; single dose) shows no apparent toxic effects in healthy BALB/c mice (male, 7 weeks old) during a 72 h observation period[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Healthy BALB/c mice (male, 7 weeks old)[1]
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Dosage:80 mg/kg
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Administration:i.v.; single dose
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Result:Distributed to the mouse brain with a brain-to-plasma partition coefficient of 0.017.
Achieved complete LMP2:AR-01 adduct formation and approximately 70% LMP2 activity inhibition in the brain within 5 min postdose.
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Animal Model:Healthy BALB/c mice (male, 7 weeks old)[1]
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Dosage:150 mg/kg
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Administration:i.p.; single dose
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Result:Achieved approximately 54% bioavailability and complete LMP2:AR-01 adduct formation in the mouse brain at 6 h postdose.
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Animal Model:Healthy BALB/c mice (male, 7 weeks old)[1]
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Dosage:150 mg/kg
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Administration:p.o.; single dose
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Result:Achieved approximately 10% oral bioavailability and approximately 71% LMP2:AR-01 adduct formation in the mouse brain.
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Animal Model:Aged C57BL/6 mice (female, 8 months old)[1]
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Dosage:20 mg/kg
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Administration:i.p.; twice weekly for 3 weeks
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Result:Achieved cumulative brain LMP2 occupancy (approximately 46% adduct formation at day 21).
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Animal Model:5xFAD mice (4 months old, both sexes)[1]
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Dosage:20 mg/kg
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Administration:i.p.; twice weekly for 3 weeks
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Result:Improved spatial memory performance and rescued reactive astrocytes.
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Animal Model:Healthy BALB/c mice (male, 7 weeks old)[2]
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Dosage:150 mg/kg
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Administration:p.o.; single dose
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Result:Inhibited approximately 90% of blood LMP2 activity and 21% of brain LMP2 activity at 6 h postdose.
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Animal Model:Healthy BALB/c mice (male, 7 weeks old)[2]
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Dosage:40 mg/kg
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Administration:i.v.; single dose
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Result:Could be detected in brain, liver, kidney, and spleen at 2 h postdose, but could not detected in lung tissues.
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Animal Model:Healthy BALB/c mice (male, 7 weeks old)[2]
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Dosage:5-100 mg/kg
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Administration:i.v.; single dose
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Result:Showed no apparent toxic effects during a 72 h observation period.
Chemical Information
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No. CAS 3056058-96-6
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Peso molecular 469.55
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Fòrmula C23H36FN3O6
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SMILES
F[C@@H]1C[C@@H](C(N[C@@H](COCCCCCC2=O)C(N[C@@H](CC(C)C)C([C@]3(C)OC3)=O)=O)=O)N2C1
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Thapa Magar TB, et al. Pharmacokinetics, Target Engagement of an Immunoproteasome Subunit Low-Molecular-Mass Polypeptide 2 (LMP2) Inhibitor AR-01, and Its Anti-Alzheimer's Effects in Rodents. ACS Pharmacol Transl Sci. 2026 Jun 29;9(7):1869-1880. [Content Brief]
[2]. Park JE, et al. Brain-Permeable Immunoproteasome-Targeting Macrocyclic Peptide Epoxyketones for Alzheimer's Disease. J Med Chem. 2024 May 9;67(9):7146-7157. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
LMP2-IN-1 Related Classifications
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