PI-1840 - CAS 1401223-22-0
Catalog number: 1401223-22-0
Category: Inhibitor
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Molecular Formula:
C22H26N4O3
Molecular Weight:
394.47
COA:
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Targets:
Proteasome
Description:
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.
Purity:
>98%
Synonyms:
PI-1840; PI 1840; PI1840
MSDS:
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InChIKey:
ZVVXAODXPVWGMF-UHFFFAOYSA-N
InChI:
InChI=1S/C22H26N4O3/c1-4-6-17-8-10-19(11-9-17)28-15-21(27)26(16(2)3)14-20-24-22(25-29-20)18-7-5-12-23-13-18/h5,7-13,16H,4,6,14-15H2,1-3H3
Canonical SMILES:
CCCC1=CC=C(C=C1)OCC(=O)N(CC2=NC(=NO2)C3=CN=CC=C3)C(C)C
1.Discovery of PI-1840, a novel noncovalent and rapidly reversible proteasome inhibitor with anti-tumor activity.
Kazi A1, Ozcan S, Tecleab A, Sun Y, Lawrence HR, Sebti SM. J Biol Chem. 2014 Apr 25;289(17):11906-15. doi: 10.1074/jbc.M113.533950. Epub 2014 Feb 25.
The proteasome inhibitor bortezomib is effective in hematologic malignancies such as multiple myeloma but has little activity against solid tumors, acts covalently, and is associated with undesired side effects. Therefore, noncovalent inhibitors that are less toxic and more effective against solid tumors are desirable. Structure activity relationship studies led to the discovery of PI-1840, a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nm) over trypsin-like and peptidylglutamyl peptide hydrolyzing (IC50 values >100 μm) activities of the proteasome. Furthermore, PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Mass spectrometry and dialysis studies demonstrate that PI-1840 is a noncovalent and rapidly reversible CT-L inhibitor. 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.Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors.
Ozcan S1, Kazi A, Marsilio F, Fang B, Guida WC, Koomen J, Lawrence HR, Sebti SM. J Med Chem. 2013 May 23;56(10):3783-805. doi: 10.1021/jm400221d. Epub 2013 May 13.
Screening of the 50000 ChemBridge compound library led to the identification of the oxadiazole-isopropylamide 1 (PI-1833) which inhibited chymotrypsin-like (CT-L) activity (IC50 = 0.60 μM) with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L). LC-MS/MS and dialysis show that 1 is a noncovalent and rapidly reversible CT-L inhibitor. Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 = 27 nM). Detailed SAR studies indicate that the amide moiety and the two phenyl rings are sensitive toward modifications. Hydrophobic residues, such as propyl or butyl in the para position (not ortho or meta) of the A-ring and a m-pyridyl group as B-ring, significantly improve activity. Compound 11ad (IC50 = 0.37 μM) is more potent than 1 (IC50 = 3.5 μM) at inhibiting CT-L activity in intact MDA-MB-468 human breast cancer cells and inhibiting their survival.
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CAS 1401223-22-0 PI-1840

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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 M...

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CAS 1401223-22-0 PI-1840

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