ONX-0914 (PR-957)

ONX-0914 (PR-957) is a specific inhibitor of the immunoproteasome subunits low molecular weight polypeptide 7 (LMP7) and low molecular weight polypeptide 2 (LMP2), with IC₅₀ values of 0.34μM and 0.0057μM, respectively ^[1]. Immunoproteasome is a form of proteasome-generated peptide presented to cytoplasmic associated T cells on major histocompatibility complex (MHC) Class I molecules, which selectively induces conformational changes in the S1 binding pocket of LMP7 ^[2]. ONX-0914 is often used in tumor immunotherapy and the research of autoimmune diseases ^[3].

In vitro, ONX-0914 (0-1μM) acted on LN229, GBM 8401 and U87MG cells for 24 hours respectively, significantly inhibiting their cell viability. Meanwhile, the levels of p53 and phosphorylated p53 were enhanced, inducing apoptosis and autophagy in glioblastoma cells ^[4]. After treating PBMCs of normal healthy donors with ONX-0914 (0.2μM) for 1 hour, the production of interferon -γ (IFN-γ) and interleukin-2 (IL-2) by activated monocytes was significantly blocked ^[5].

In vivo, ONX-0914 (15mg/kg) was injected through the tail vein to treat SEM-GFP-luc cells xenograft mice for 12 days, significantly delaying the growth of orthotopic ALL xenograft tumors in mice ^[6]. When ONX-0914 (10mg/kg) was injected via the tail vein for the treatment of mice with chronic myocarditis induced by CVB3 31-1-93 virus, it led to an increase in serum troponin T (TnT) levels, an increase in cardiac tissue inflammation and monocyte infiltration, and a significant increase in viral load, exacerbating virus-mediated cardiac tissue damage ^[7].

References:
[1] de Bruin G, Huber E M, Xin B T, et al. Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes[J]. J Med Chem, 2014, 57(14):6197-6209.
[2] 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 inhibitors[J]. Haematologica, 2013, 98(12):1896-1904.
[3] Basler M, Lindstrom M M, LaStant J J, et al. Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity[J]. EMBO Rep, 2018, 19(12)
[4] Chang H H, Lin Y H, Chen T M, et al. ONX-0914 Induces Apoptosis and Autophagy with p53 Regulation in Human Glioblastoma Cells[J]. Cancers (Basel), 2022, 14(22)
[5] 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 arthritis[J]. Nature Medicine, 2009, 15(7):781-787.
[6] Jenkins T W, Downey-Kopyscinski S L, Fields J L, et al. Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein[J]. Scientific Reports, 2021, 11(1):10883.
[7] Neumaier H L, Harel S, Klingel K, et al. ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage[J]. Cells, 2020, 9(5).

ONX-0914 (PR-957) 是免疫蛋白酶体亚基低分子量多肽7（LMP7）和低分子量多肽2（LMP2）的特异性抑制剂，IC₅₀分别为0.34μM、0.0057μM^[1]。免疫蛋白酶体是一种在主要组织相容性复合体（MHC）I类分子上呈递给胞质相关T细胞的蛋白酶体生成肽的形式，选择性地诱导LMP7的S1结合口袋的构象变化^[2]。ONX-0914常用于肿瘤免疫治疗及自身免疫性疾病研究^[3]。

在体外，ONX-0914（0-1μM）分别作用于LN229、GBM8401和U87MG细胞24小时，显著抑制其细胞活力；同时增强了p53和磷酸化p53的水平，诱导胶质母细胞瘤细胞发生凋亡与自噬^[4]。使用ONX-0914（0.2μM）处理正常健康供体的PBMCs细胞1小时后，显著阻断了活化的单核细胞产生干扰素-γ和白细胞介素-2^[5]。

在体内，ONX-0914（15mg/kg）通过尾静脉注射治疗SEM-GFP-luc细胞异种移植小鼠12天，显著延迟了小鼠原位ALL异种移植肿瘤的生长^[6]。ONX-0914（10mg/kg）通过尾静脉注射用于治疗通过CVB3 31-1-93病毒诱导的慢性心肌炎小鼠时，导致血清肌钙蛋白T水平升高，心脏组织炎症和单核细胞浸润增加，病毒载量显著上升，加剧了病毒介导的心脏组织损伤^[7]。