Biological Activity
onx-0914, previously known as pr-975, is a potent inhibitor of immunoproteasome, a form of proteasome generating peptides presented on major histocompatibility complex (mhc) class i molecule to cytotixic t cells, which selectively induces conformational changes in the s1 binding pocket of the immunoproteasome subunit β5i (low molecular mass polypeptide 7/lmp7) rather than the constitutive proteasome subunit β5 in human and mouse cells. onx-0914 is able to block the production of proinflammatory cytokines from human peripheral blood mononuclear cells (pbmcs), activate mouse splenocytes, inhibit il-17-producing t cells under th17-polarizing cytokines in vitro, and attenuate disease progression of diabetes, arthritis, and colitis in mouse models.denise niewerth, niels e. franke, gerrit jansen, yehuda g. assaraf, johan van meerloo, christopher. kirk, jeremiah degenhardt, janet anderl, aaron d. schimmer, sonja zweegman, valerie de haas, terzah m. horton, gertjan j.l. kaspers, and jacqueline cloos. higer ratio immune vs. constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. haematologica 2013.khalid w. kalim, michael basler, christopher j. kirk and marcus groettrup. immunoproteasome subunit lmp7 deficiency and inhibition suppresses th1 and th17 but enhances regulatory t cell differentiation. j immunol 2012; 189:4182-4193
Enzyme inhibitor
This potent protease inhibitor (FW = 580.67 g/mol; CAS 960374-59-8; Solubility: 100 mg/mL DMSO or H2O), also known as PR-957 and N-[2-(4- morpholinyl)acetyl]-L-alanyl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2- oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-tyrosinamide, targets (IC50 = 10 nM) the chymotrypsin-like protease activity of immunoproteasomes, a distinct class of proteasome found mainly in monocytes and lymphocytes. These specialized proteasomes shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). ONX-0914 shows minimal cross-reactivity for the constitutive proteasome. Selective inhibition blocks production of Interleukin-23 (IL-23) by activated monocytes and interferon-γ and IL-2 by T cells.
