1401223-22-0

Basic information

• Product Name: PI-1840
• Synonyms: PI-1840;N-isopropyl-2-(4-propylphenoxy)-N-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)acetamide;N-(1-methylethyl)-2-(4-propylphenoxy)-N-[[3-(3-pyridinyl)-1,2,4-oxadiazol-5-yl]methyl]-acetamide
• CAS NO: 1401223-22-0
• Molecular Formula: C₂₂H₂₆N₄O₃
• Molecular Weight: 394.46684
• EINECS: 604-604-1
• Product Categories: Inhibitors
• Mol File: 1401223-22-0.mol
• Article Data: 2

Chemical Properties

• Appearance: /
• Solubility: insoluble in H2O; ≥4.44 mg/mL in EtOH with ultrasonic; ≥70.7 mg/mL in DMSO
• CAS DataBase Reference: PI-1840(CAS DataBase Reference)
• NIST Chemistry Reference: PI-1840(1401223-22-0)
• EPA Substance Registry System: PI-1840(1401223-22-0)

Safety Data

• Hazardous Substances Data: 1401223-22-0(Hazardous Substances Data)

Usage

Uses

PI 1840 is a novel rapidly reversible proteasome inhibitor with antitumor activity.

Biological Activity

pi-1840 is a potent and selective inhibitor of proteasome with ic50 value of 27 nm for chymotrypsinlike (ct-l) activity [1].the 26s proteasome consists of a 19s regulatory particle (rp) and a 20s core particle. the 26s proteasome have three main catalytic activities: chymotrypsin-like (ct-l), peptidylglutamyl peptide hydrolyzing-like (pgph-l) and trypsin-like (t-l) activities. ct-l activity plays an important role in the degradation of tumor suppressor and apoptotic proteins [1].pi-1840 is a rapidly reversible and non-covalent proteasome ct-l inhibitor. pi-1840 exhibited excellent selectivity for ct-l over pgph-l and t-l activities. in mda-mb-468 human breast cancer cells, pi-1840 inhibited the ct-l activity with ic50 value of 0.37 μm and inhibited cell survival/proliferation [1]. also, pi-1840 exhibited 121-fold selectivity for the constitutive 20 s proteasome over the immunoproteasome with ic50 values of 18 and 2170 nm, respectively. in mda-mb-468 cells, pi-1840 caused the accumulation of ct-l substrates iκb-α, p27 and bax. also, pi-1840 reduced the levels of survivin, p-akt and ser(p)-6 and induced apoptosis through poly(adp-ribose) polymerase cleavage and caspase-3 activation [2].in nude mice bearing human breast tumor, pi-1840 (150 mg/kg/day, i.p, daily) inhibited tumor growth by 85% [2].

Enzyme inhibitor

This potent proteasome inhibitor (FW = 394.38 g/mol) selectively targets its chymotrypsin-like activity, or CT-L (IC50 = 27 nM), while showing much weaker action (IC50 values >100 μM) against its Trypsin-Like (T-L) and peptidylglutamyl peptide hydrolyzing, or PGPH activities. Mass spectrometry and equilibrium dialysis show no evidence of covalent linkage of PI-1840 with any proteasomal protein component. In intact cancer cells, PI-1840 inhibits CT-L activity, inducing the accumulation of proteasome substrates p27, Bax and IκB-α, thereby inhibiting survival pathways and viability, and inducing apoptosis. PI=1840 is also >100x more active against the constitutive proteasome, compared to immunoproteasome.

references

[1]. ozcan s, kazi a, marsilio f, et al. oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors. j med chem, 2013, 56(10): 3783-3805.[2]. kazi a, ozcan s, tecleab a, et al. discovery of pi-1840, a novel noncovalent and rapidly reversible proteasome inhibitor with anti-tumor activity. j biol chem, 2014, 289(17): 11906-11915.

Upstream product

• 645-56-7 4-n-Propylphenol 
• 15328-03-7 5-(chloromethyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole 
• 1401223-72-0 (Z)-N'-(2-chloroacetoxy)nicotinimidamide 
• 1594-58-7 (Z)-N'-hydroxy(pyridin-3-yl)methanimidamide 
• 100-54-9 pyridine-3-carbonitrile 
• 7507-32-6 2-(4-propylphenoxy)acetic acid 
• 1401223-55-9 tert-butyl 2-(4-propylphenoxy)acetate 
• 1092299-88-1 (4-propylphenoxy)acetyl chloride 
• 1184229-50-2 N-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)propan-2-amine 

Relevant articles and documents

Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors

Screening of the 50 000 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. The activity of 11ad warrants further preclinical investigation of this class as noncovalent proteasome inhibitors.