KZR-504
目录号 : GC31899
KZR-504是具有口服活性的、高度选择性的免疫原体低分子质量多肽2(LMP2)的抑制剂、其对LMP2和LMP7的IC50值分别为51nM,4.274μM。
Cas No.:1629052-78-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
KZR-504 is a highly selective and orally active inhibitor of immunoproteasome low molecular mass polypeptide 2 (LMP2), with IC50s of 51 nM, 4.274 μM for LMP2 and LMP7, respectively.
Evaluating the inhibition of LMP2, and antitargets LMP7 and β5, in mouse tissues reveals that KZR-504 (compound 12) is both selective and potent in vivo with >50% target inhibition achieved at >1 mg/kg in all tissues tested except brain[1].
[1]. Johnson HWB, et al. Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit. ACS Med Chem Lett. 2017 Mar 9;8(4):413-417.
| Cas No. | 1629052-78-3 | SDF | |
| Canonical SMILES | O=C(N[C@@H](CO)C(N[C@@H](CC1=CC=CC=C1)C([C@]2(CO2)C)=O)=O)C(N3)=CC=CC3=O | ||
| 分子式 | C21H23N3O6 | 分子量 | 413.42 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C, protect from light, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4188 mL | 12.0942 mL | 24.1885 mL |
| 5 mM | 0.4838 mL | 2.4188 mL | 4.8377 mL |
| 10 mM | 0.2419 mL | 1.2094 mL | 2.4188 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Co-inhibition of immunoproteasome subunits LMP2 and LMP7 enables prevention of transplant arteriosclerosis
Aims: The loss of vascular wall cells in allotransplanted arteries is the initial event leading to transplant arteriosclerosis (TA) and ensuing loss of allograft function. Pharmacological agents able to prevent TA are currently lacking. We previously showed that selective inhibition of the immunoproteasome prevented the chronic rejection of renal allografts. However, the role and mechanisms of selective inhibition of a single immunoproteasome subunit suffices to prevent immune-mediated vascular allograft rejection and TA is not clear. Methods and results: The effect and potential mechanism of combined or individual inhibition of peptidolytically active immunoproteasome LMP7 (β5i) and LMP2 (β1i) subunits on immune rejection-mediated TA was investigated using the epoxyketone inhibitor ONX 0914, and the recently developed LMP7-selective inhibitor KZR-329 and LMP2-selective inhibitor KZR-504 in a rat aorta transplantation model. We find that co-inhibition of LMP7 and LMP2 in allogeneic recipients significantly suppressed T cell activation and function by expressing inhibitory surface markers and then activating inhibitory signals. Moreover, co-inhibition of LMP7 and LMP2 substantially reduced the number of IgG secreting cells and plasma cells and production of alloantibodies through activating the unfolded protein response and incapacitating the survival niche of plasma cells in the bone marrow. Consequentially, the accumulation of inflammatory cytokines, complement and antibodies is reduced and the apoptosis of vascular wall cells decreased in aortic allografts via LMP7 and LMP2 co-inhibition with ONX 0914 treatment or combined KZR-329 and KZR-504 treatment. However, neither individual inhibition of LMP7 by KZR-329 nor individual inhibition of LMP2 by KZR-504 showed suppression of immune rejection and TA. Conclusions: We define a critical role of LMP7 and LMP2 in TA and strongly propose co-inhibition of both immunoproteasome subunits as promising therapeutic approach to suppress TA and allograft rejection. Translational perspective: So far, effective pharmacological agents to treat transplant arteriosclerosis and ensuing chronic allograft rejection are lacking. Co-inhibition, but neither individual inhibition, of peptidolytically active immunoproteasome LMP7 and/nor LMP2 subunits using epoxyketone inhibitors significantly prevents transplant arteriosclerosis by suppressing T cell-mediated and humoral immune rejection. LMP7 and LMP2 are identified as targets for the prevention of chronic immune rejection after transplantation. Pharmaceuticals that co-inhibit immunoproteasome subunits are currently clinically tested as drugs against autoimmunity. These drugs hold great promise for suppressing transplant arteriosclerosis and allograft rejection, potentially improving prognosis of patients after solid organ transplantation.
Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit
Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo. Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor KZR-504 (12).