PI-1840

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].

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.

Discovery of PI-1840, a novel noncovalent and rapidly reversible proteasome inhibitor with anti-tumor activity.[Pubmed:24570003]

J Biol Chem. 2014 Apr 25;289(17):11906-15.

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 mum) 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 IkappaB-alpha, inhibits survival pathways and viability, and induces apoptosis. Furthermore, PI-1840 sensitizes human cancer cells to the mdm2/p53 disruptor, nutlin, and to the pan-Bcl-2 antagonist BH3-M6. Finally, in vivo, PI-1840 but not bortezomib suppresses the growth in nude mice of human breast tumor xenografts. These results warrant further evaluation of a noncovalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors.

PI-1840 is 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.

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