Home Proteases Proteasome inhibitor PI-1840 For research use only.

PI-1840

PI-1840 is a reversible and selective chymotrypsin-like (CT-L) inhibitor with IC50 of 27 nM with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L).

PI-1840 Chemical Structure

PI-1840 Chemical Structure

CAS No. 1401223-22-0

Purity & Quality Control

Batch: S746201 DMSO]78 mg/mL]false]Ethanol]33 mg/mL]false]Water]Insoluble]false Purity: 99.20%
99.20

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Biological Activity

Description PI-1840 is a reversible and selective chymotrypsin-like (CT-L) inhibitor with IC50 of 27 nM with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L).
Targets
Chymotrypsin-like proteasome [1]
27 nM
In vitro
In vitro PI-1840 potently inhibits proteasomal CT-L activity with IC50 of 0.37 μM in intact human MDA-MB-468 cancer cells, and inhibits proliferation/survival of human MDA-MB-468 cells. [1] In intact cancer cells, PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax, and IκB-α, inhibits survival pathways and viability, and induces apoptosis. [2]
Kinase Assay CT-L, T-L, PGPH-L proteolytic activity assays
In the high-throughput screen, fluorogenic peptides are used as substrates to assay (at 10 μM) the 50,000 compounds library from ChemBridge for inhibitory activity against the CT-L proteolytic activity of the purified rabbit 20S proteasome. To test for selectivity for CT-L over T-L and PGPH-L the corresponding fluorogenic peptides are used. Briefly, 1 nM of purified 20S rabbit proteasome is incubated with 20 μM Suc-Leu-Leu-Val-Tyr-AMC for the CT-L activity, Bz-Val-Gly-Arg-AMC for the T-L activity, and benzyloxycarbonyl Z-Leu-Leu-Glu-AMC for the PGPH-L activity for 1 h at 37 °C in 100 μL of assay buffer (50 mM Tris-HCl, pH 7.6) with or without compound. After incubation, production of hydrolyzed 7-amido-4-methyl-coumarin (AMC) groups is measured using a WALLAC Victor2 1420 Multilabel Counter with an excitation filter of 355 nm and an emission filter of 460 nm. The amount of AMC released is within the linear range. Bortezomib is used as a positive control for IC50 determinations. To determine proteasome activity in whole cell, extracts (5 μg) from cultured cell lysate is used instead of 20S rabbit proteasome, and followed the same assay mentioned above.
Cell Research Cell lines MDA-MB-468 cells
Concentrations ~200 μM
Incubation Time 5 days
Method Cells are plated in 96-well plates in 100 μL medium and allowed to attach overnight. Cells are then incubated for 120 h with varying concentrations of inhibitors. Media is aspirated and replaced with 100 μL complete media containing 1 mg/ml MTT and incubated for three hours at 37 °C in 5% CO2 humidified incubator. Media is then aspirated and DMSO is added. Cells are incubated for 10 min at room temperature while shaking, and the absorbance is determined at 540 nm using a μQuant spectrophotometric plate reader. The IC50 values are determined using equation under CT-L, T-L, PGPH-L proteolytic activity assays.
In Vivo
In vivo PI-1840 (150 mg/kg i.p.) inhibits the tumor growth in mice of MDA-MB-231 breast tumors. [2]
Animal Research Animal Models Nude mice bearing human breast cancer MDA-MB-231 xenografts
Dosages ~150 mg/kg daily
Administration i.p.

Chemical Information & Solubility

Molecular Weight 394.47 Formula

C22H26N4O3
CAS No. 1401223-22-0 SDF Download PI-1840 SDF
Smiles CCCC1=CC=C(C=C1)OCC(=O)N(CC2=NC(=NO2)C3=CN=CC=C3)C(C)C
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 78 mg/mL ( (197.73 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 33 mg/mL

Water : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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