immunoproteasome lmp7

LMP7-IN-1 may used in the research of inflammatory and autoimmune diseases, neurodegenerative diseases, proliferative diseases and cancer, is an inhibitor of immunoproteasome (LMP7).

ONX-0914 (PR-957) is a potent and highly specific immunoproteasome inhibitor with minimal cross-reactivity to the constitutive proteasome.

Oprozomib (PR-047) (ONX 0912) , an inhibitor for CT-L activity of 20S proteasome β5(IC50=36 nM) LMP7(IC50=82 nM), is orally bioavailable. Oprozomib also has potential antineoplastic activity.

KZR-504 is a selective inhibitor of immunoproteasome low molecular mass polypeptide 2 (LMP2) (IC50s: 51 nM, 4.274 μM for LMP2 and LMP7, respectively).

KZR-616, a first-in-class inhibitor of the immunoproteasome, selectively targets the LMP7 (IC50: 39/57 nM=hLMP7/mLMP7) and LMP2 (IC50: 131/179 nM=hLMP7/mLMP7) subunits of the immunoproteasome. KZR-616 has the potential for the research of multiple autoimmune diseases[1][2]. KZR-616 also inhibits MECL-1 subunit (IC50=623 nM) and constitutive proteasome β5 subunit (IC50=688 nM). KZR-616 maintains LMP7 and LMP2 selective inhibition in MOLT-4 cells. KZR-616 (250 nM) shows a comparable cytokine inhibition profile peripheral blood mononuclear cells (PBMC)[1].KZR-616 is an immunoproteasome-selective inhibitor identified based on the optimization of ONX-0914 and PR-924 [3]. KZR-616 (5 mg/kg; i.v.; dosing was repeated on days 6, 8, 11, and 13) shows efficacy in the anticollagen antibody induced arthritis (CAIA) model[1]. [1]. Johnson HWB, et al. Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-(( S)-3-(Cyclopent-1-en-1-yl)-1-(( R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-(( S)-2-(2-morpholinoacetamido)propanamido)propenamide). J Med Chem. 2018 Dec 27;61(24):11127-11143. [2]. Muchamuel T, et al. FRI0296 Kzr-616, a selective inhibitor of the immunoproteasome, blocks the disease progression in multiple models of systemic lupus erythematosus (SLE). Annals of the Rheumatic Diseases 2018;77:685. [3]. Xi J, et al. Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases. Eur J Med Chem. 2019;182:111646.

Zetomipzomib maleate (KZR-616), a novel immunoproteasome inhibitor, effectively and selectively inhibits the LMP7 subunit (hLMP7 mLMP7 IC50: 39 57 nM) and LMP2 subunit (hLMP7 mLMP7 IC50: 131 179 nM) of the immunoproteasome. This compound shows promising potential for research in various autoimmune diseases.

ONX-0914 (PR-957) TFA is a selective, noncompetitive, irreversible inhibitor of the chymotrypsin-like subunit (LMP7) of the immunoproteasome, effectively blocking cytokine production and mitigating experimental arthritis progression. With a K_i value of 5.2 μM against the mycobacterial proteasome, ONX-0914 TFA also reactivates latent HIV-1 by inducing p-TEFb activation through HSF-1 mediation [1] [2] [3].

LMP7 LMP2-IN-1 (Compound 19) is an orally effective inhibitor targeting the immunoproteasome subunits LMP7 and LMP2, with respective IC50 values of 257 and 10 nM. This compound reduces the production of antibodies and downregulates the B cells in the germinal centers of the spleen and plasma cells in NP-OVA immunized mice. It has potential applications in the study of autoimmune diseases.