ONX 0912 is an orally bioavailable proteasome inhibitor. It potently targets the chymotrypsin-like activity of the 20S proteasome subunits β5 and LMP7 (IC50s = 36 and 82 nM, respectively). ONX 0912 inhibits the growth of multiple myeloma cells at nanomolar concentrations while not decreasing the viability of normal peripheral blood mononuclear cells at 1 μM. It blocks the growth of xenografted human multiple myeloma cells in mice when given orally. ONX 0912 has potential applications in certain types of cancer as well as other diseases that require proteasome activity.
This orally active inhibitor (FW = 532.61 g/mol; CAS 935888-69-0; Solubility: 105 mg/mL DMSO, <1 mg/mL H2O), also known as ONX 0912 and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)-ethyl]-Lserinamide, selectively targets the chymotrypsin-like (CT-L) activity of 20S proteasome β5 (IC50 = 36 nM) and 20S proteasome LMP7 (IC50 = 82 nM). In animal tumor model studies, ONX 0912 significantly reduced tumor progression and prolonged survival. Immununostaining of multiple myeloma tumors from ONX 0912-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Oprozomib is distinct from carfilzomib, even though the same chemistry was employed to selectively target the proteasome. Oprozomib is under development as an oral therapy for hematologic malignancies, including multiple myeloma, and for patients with recurrent or refractory solid tumors (See also Carfilzomib).
