Oprozomib

Oprozomib (ONX-0912; PR-047) is a potent, orally bioavailable proteasome inhibitor that inhibits chymotrypsin-like (CT-L) activity of 20S proteasome β5/LMP7 with IC50 of 36/82 nM; triggers apoptosis in MM cells, associated with PARP cleavage and caspase activation, causes in vitro and in vivo cytotoxicity in multiple myeloma, also enhances anti-MM activity of bortezomib, lenalidomide dexamethasone, or pan-histone deacetylase inhibitor.Blood Cancer Phase 2 Clinical (In Vitro) :Oprozomib inhibits 20S chymotrypsin-like (CT-L) with an IC50 of 55 ± 19 nM. Oprozomib inhibits human leukemia Molt-4 cells CT-L with an IC50 of 66 nM.Oprozomib (ONX 0912; 1-1000 nM; 48 hours) significantly decreases the viability of human multiple myeloma (MM) cell lines.The anti-MM activity of Oprozomib is associated with activation of caspase-8, caspase-9, caspase-3, and PARP. (In Vivo) :Oprozomib (PR-047) selectively inhibits chymotrypsin-like (CT-L) activity of both the constitutive proteasome (β5) and immunoproteasome (LMP7) and demonstrates an absolute bioavailability of up to 39% in rodents and dogs.Oprozomib promotes antitumor activity in multiple animal models by oral administration at doses below the maximum tolerated dose (MTD) .Oprozomib (30 mg/kg by oral gavage once daily for 5 consecutive days followed by 2 days of rest) treatment decreases tumor burden in C57Bl/6 and NOD.SCID.IL2Rγ-/- mice.