immunoproteasome β5

UK-101属于小分子抑制剂，是一种免疫蛋白酶体β1i（LMP2）亚基的选择性抑制剂（IC50=104 nM），对β1c和β5亚基分别具有144倍和10倍的选择性。该化合物可诱导细胞凋亡，具有抗肿瘤活性，可用于前列腺癌相关研究。

Immunoproteasome-IN-2 是一种选择性免疫蛋白酶体抑制剂，其对LMP7亚基的IC50为232.3 nM，对β5亚基的IC50为9384.9 nM。它对LMP2和MECL-1亚基同样具有一定的抑制活性。在关节炎小鼠模型中，Immunoproteasome-IN-2 显示出抗炎效果，并且在毒理学研究中表现出良好的安全性，肝脏毒性和血液毒性均较低。Immunoproteasome-IN-2 的LMP7/β5选择性与其较低的系统毒性直接相关，适用于关节炎相关研究。

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.