Background:

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].

参考文献:
[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.