ONX-0914 TFA

The immunoproteasome is a specialized, inducible proteasome that generates peptides presented on major histocompatibility complex (MHC) class I molecules to cytotoxic T cells. Stimulation of cells with inflammatory cytokines such as IFN-γ leads to the replacement of constitutive catalytic proteasome β subunits with inducible β subunits (β1i (LMP2), β2i (MECL1), and β5i (LMP7)), which are required for the production of certain MHC class I-restricted T cell epitopes. ONX 0914 is a selective inhibitor of the β5i (LMP7) subunit of the immunoproteasome (IC₅₀s = 65 and 73 nM for mouse and human, respectively) and demonstrates significantly weaker activity at the β5 subunit of the constitutive proteasome (IC₅₀s = 0.92 and 1.04 ?M for mouse and human, respectively).^1,2 It can block the production of IL-23 by activated monocytes and the production of IFN-γ and IL-2 by T cells.¹ ONX 0914 can also inhibit IL-17-producing T cells under T_H17-polarizing conditions in vitro and reduce T_H1 and T_H17 cell differentiation in vivo.³ This compound has been shown to attenuate disease progression in several experimental models of autoimmune disorders as well as in some hematologic malignancies.^1,4,5,6

1.Muchamuel, T., Basler, M., Aujay, M.A., et al.A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritisNat. Med.15(7)781-787(2009) 2.Huber, E.M., Basler, M., Schwab, R., et al.Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificityCell148(4)727-738(2012) 3.Kalim, K.W., Basler, M., Kirk, C.J., et al.Immunoproteasome subunit LMP7 deficiency and inhibition suppresses Th1 and Th17 but enhances regulatory T cell differentiationJ. Immunol.189(8)4182-4193(2012) 4.Basler, M., Daiee, M., Moll, C., et al.Prevention of experimental colitis by a selective inhibitor of the immunoproteasomeJ. Immunol.185(1)634-641(2010) 5.Niewerth, D., Franke, N.E., Jansen, G., et al.Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitorsHaematologica98(12)1896-1904(2013) 6.Niewerth, D., Kaspers, G.J., Assaraf, Y.G., et al.Interferon-γ-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell linesJ. Hematol. Oncol.7(1)1-15(2014)