An inhibitor of NLRP3 inflammasome activation
MCC950 is a potent, selective, small molecule inhibitor of NLRP3. MCC950 blocks canonical and non-canonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibits NLRP3 but not AIM2, NLRC4 or NLRP1 activation. MCC950 reduces Interleukin-1p (IL-1β) production in vivo and attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescues neonatal lethality in a mouse model of CAPS and is active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for the further study of the NLRP3 inflammasome in human health and disease.[1]
The half-maximal inhibitory concentration (IC50) of MCC950 in BMDM was approximately 7.5 nM, while in HMDM it had a similar inhibitory capacity (IC50 = 8.1 nM). Cells were first primed with LPS then pre-treated with MCC950 and lastly stimulated with the NLRP3 stimulus ATP. Treating cells with nanomolar concentrations of MCC950 dose dependently inhibited the release of IL-1β in BMDM, HMDM and PBMC. [1]
Mice were pre-treated with MCC950 one hour before i.p. injection of LPS and were assessed two hours later. Pre-treatment with MCC950 reduced serum concentrations of IL-1β and IL-6 while it did not considerably decrease the amount of TNF-α, indicating that MCC950 is active in vivo.Besides, treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1βexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice.[1,2]
参考文献:
[1]. Coll, Rebecca C et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature medicine vol. 21,3 (2015): 248-55.
[2]. Zhai, Yadong et al. Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice. Molecules (Basel, Switzerland) vol. 23,3 522. 27 Feb. 2018.
MCC950 是一种有效的选择性小分子 NLRP3 抑制剂。 MCC950 在纳摩尔浓度下阻断经典和非经典 NLRP3 激活。 MCC950 特异性抑制 NLRP3，但不抑制 AIM2、NLRC4 或 NLRP1 激活。 MCC950 减少体内白细胞介素-1p (IL-1β) 的产生并减轻实验性自身免疫性脑脊髓炎 (EAE) 的严重程度，EAE 是一种多发性硬化症的疾病模型。此外，MCC950 治疗可挽救 CAPS 小鼠模型中的新生儿致死率，并且在 Muckle-Wells 综合征患者的离体样本中具有活性。因此，MCC950 是一种潜在的治疗 NLRP3 相关综合征（包括自身炎症和自身免疫性疾病）的药物，也是进一步研究 NLRP3 炎性体在人类健康和疾病中的作用的工具。[1]
MCC950 在 BMDM 中的半数最大抑制浓度 (IC50) 约为 7.5 nM，而在 HMDM 中具有相似的抑制能力 (IC50 = 8.1纳米）。细胞首先用 LPS 引发，然后用 MCC950 预处理，最后用 NLRP3 刺激物 ATP 刺激。用纳摩尔浓度的 MCC950 处理细胞会剂量依赖性地抑制 BMDM、HMDM 和 PBMC 中 IL-1β 的释放。 [1]
小鼠在腹腔注射前一小时用 MCC950 进行预处理。注射 LPS 并在两小时后进行评估。用 MCC950 预处理降低了 IL-1β 和 IL-6 的血清浓度，同时没有显着降低 TNF-α 的量，表明 MCC950 在体内具有活性。此外，用 NLRP3 炎性体抑制剂 MCC950 治疗 db/db 小鼠改善了焦虑和抑郁样行为以及认知功能障碍，并逆转了海马中增加的 NLRP3、ASC 和 IL-1β 表达水平和 caspase-1 活性。此外，MCC950 治疗显着改善了 db/db 小鼠的胰岛素敏感性。[1,2]
| Cell experiment [1]: | |
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Cell lines |
Bone marrow, HEK293T cells |
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Preparation Method |
MCC950 sodium salt is highly soluble in aqueous solutions |
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Reaction Conditions |
0.001–10 μM, 30 min |
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Applications |
The half-maximal inhibitory concentration (IC50) of MCC950 in BMDM was approximately 7.5 nM, while in HMDM it had a similar inhibitory capacity (IC50 = 8.1 nM). |
| Animal experiment [2]: | |
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Animal models |
C57BL/6 mice |
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Preparation Method |
MCC950 sodium salt is highly soluble in aqueous solutions. |
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Dosage form |
50 mg/kg, Intraperitoneal injection |
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Applications |
MCC950 not only inhibits NLRP3 in vivo and attenuates EAE severity, but also rescues a mouse model of CAPS and inhibits NLRP3 in human MWS cells. |
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参考文献: [1]. Coll, Rebecca C et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature medicine vol. 21,3 (2015): 248-55. [2]. Zhai, Yadong et al. Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice. Molecules (Basel, Switzerland) vol. 23,3 522. 27 Feb. 2018. |
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