MLT-943
目录号 : GC62464
MLT-943 是一种有效的、选择性的、口服活性的 MALT1 protease 抑制剂。MLT-943 可抑制 PBMC 或全血中 IL-2 的分泌，PBMC 中抑制的 IC50 值为 0.07~0.09 μM，全血中抑制的 IC50 值为 0.6~0.8 μM)。MLT-943具有抗炎活性，可用于 FcgR 介导的炎症研究。
Cas No.:1832576-04-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
MLT-943 is a potent, selective and orally active MALT1 protease inhibitor. MLT-943 inhibits stimulated-IL-2 secretion in PBMC or in whole blood with a similar IC50 across species (0.07-0.09 μM in PBMC, 0.6-0.8 μM in whole blood). MLT-943 has anti-inflammatory activities and can be used for FcgR-mediated inflammation research[1].
MLT-943 shows a high potency and selectivity in vitro. MLT-943 inhibits stimulated IL-2 secretion in PBMC or in whole blood with a similar IC50 across species (0.07-0.09 μM in PBMC, 0.6-0.8 μM in whole blood)[1].
MLT-943 (oral gavage; 10 mg/kg; QD) prophylactic treatment in the rat collagen-induced arthritis model suppresses anti-collagen antibody production, fully prevents paw swelling, and normalizes joint histology scores in rat model[1].MLT-943 (oral gavage; 5 mg/kg; QD; 10 consecutive days) effectively inhibits MALT1 protease activity and results in a progressive reduction in the frequency of Foxp3+CD25+ Treg cells in circulating CD4+ T cells, which was maximal after 7 days of treatment. And Discontinuation of MLT-943 treatment after day 10 leads to Treg frequency progressively returning to their original values within 4 days. Suboptimal doses of MLT-943 (0.1 and 0.5 mg/kg QD; p.o.) does not impact the Treg frequency[1].MLT-943 (oral gavage; 0, 5, 20 or 80 mg/kg/day; 4-13 weeks) causes a reduction in Treg and an increase in total T cell counts, in both 4- and 13-week rat toxicity studies at all dose levels. While a 4-Longer treatment induces severe immune-mediated pathology in multiple organs, with clinical onset starting around week 9 in rat[1].MLT-943 (p.o. admistration; 3 mg/kg; single dose) exhibits a good PK parameters in vivo. The Cmax values are 0.7 nM and 0.5 nM, respectively in rat and mice, respectively. And the F% are 86% and 50% in rat and mice, respective[1].For i.v. admistration the compound is formed in NMP:PEG200 (30/70); For p.o. admistration solution is formed in MC:Tween 80:Water (0.5:0.5:99) solution (Sourced from literature, for reference only)[1].
[1]. Kea Martin, et al. Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology. Front Immunol
[2]. Jean Quancard, et al. Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood. J Med Chem. 2020 Dec 10;63(23):14594-14608.
| Cas No. | 1832576-04-1 | SDF | |
| 分子式 | C16H14ClF3N6O2 | 分子量 | 414.77 |
| 溶解度 | DMSO : 250 mg/mL (602.74 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| 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 | 2.411 mL | 12.0549 mL | 24.1097 mL |
| 5 mM | 0.4822 mL | 2.411 mL | 4.8219 mL |
| 10 mM | 0.2411 mL | 1.2055 mL | 2.411 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。
Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology
Front Immunol 2020 Apr 30;11:745.PMID:32425939DOI:PMC7203682
Genetic disruption or short-term pharmacological inhibition of MALT1 protease is effective in several preclinical models of autoimmunity and B cell malignancies. Despite these protective effects, the severe reduction in regulatory T cells (Tregs) and the associated IPEX-like pathology occurring upon congenital disruption of the MALT1 protease in mice has raised concerns about the long-term safety of MALT1 inhibition. Here we describe the results of a series of toxicology studies in rat and dog species using MLT-943, a novel potent and selective MALT1 protease inhibitor. While MLT-943 effectively prevented T cell-dependent B cell immune responses and reduced joint inflammation in the collagen-induced arthritis rat pharmacology model, in both preclinical species, pharmacological inhibition of MALT1 was associated with a rapid and dose-dependent reduction in Tregs and resulted in the progressive appearance of immune abnormalities and clinical signs of an IPEX-like pathology. At the 13-week time point, rats displayed severe intestinal inflammation associated with mast cell activation, high serum IgE levels, systemic T cell activation and mononuclear cell infiltration in multiple tissues. Importantly, using thymectomized rats we demonstrated that MALT1 protease inhibition affects peripheral Treg frequency independently of effects on thymic Treg output and development. Our data confirm the therapeutic potential of MALT1 protease inhibitors but highlight the safety risks and challenges to consider before potential application of such inhibitors into the clinic.