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URMC-099

现货
Catalog No.
B4877
MLK3抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,320.00
现货
5mg
¥ 1,190.00
现货
25mg
¥ 3,600.00
现货
100mg
¥ 8,640.00
现货

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Background

URMC-099 is an orally bioavailable and brain penetrant inhibitor of MLK3 with IC50 value of 14 nM [1].

Mixed Lineage Kinase 3 (MLK3) is a member of the serine/threonine kinase family that regulate MAPK8/JNK signaling cascade and also activates ERK and p38. MLK3 activation can result in the stimulation of cell motility and migration [1] [2].

URMC-099 is a novel and orally bioavailable MLK3 inhibitor. In murine BV-2 microglial cells, URMC-099 inhibited LPS-induced TNFαrelease. In primary human monocytes, URMC-099 inhibited HIV-1 Tat-induced release of cytokines [1]. In neutrophils, URMC-099 reduced chemotaxis induced by fMLP and inhibited fMLP-stimulated F-actin formation [2].

In Tat-injected brains of mice, URMC-099 inhibited up-regulation of phospho-JNK. In HIV-1 Associated Neurocognitive Disorders (HAND) preclinical models, URMC-099 inhibited multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). URMC-099 reduced inflammatory cytokine production, protected neuronal architecture, and altered the morphologic and ultrastructural response of microglia to HIV-1 Tat exposure [1] [3]. In wild-type C57Bl/6 mice, URMC-099 inhibited fMLP-induced accumulation of neutrophils in the peritoneum [2]. In infected humanized NOD/SCID/IL2Rγc-/-mice, URMC-099 administered with nanoATV dose-dependently reduced HIV-1p24 viral load and reverse transcriptase activity, as well as the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues [4].

References:
[1].  Goodfellow VS, Loweth CJ, Ravula SB, et al. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem, 2013, 56(20): 8032-8048.
[2].  Polesskaya O, Wong C, Lebron L, et al. MLK3 regulates fMLP-stimulated neutrophil motility. Mol Immunol, 2014, 58(2): 214-222.
[3].  Marker DF, Tremblay MÈ, Puccini JM, et al. The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders. J Neurosci, 2013, 33(24): 9998-10010.
[4].  Zhang G, Guo D, Dash PK, et al. The Mixed Lineage Kinase-3 Inhibitor URMC-099 Improves Therapeutic Outcomes for Long-Acting Antiretroviral Therapy. Nanomedicine, 2015. pii: S1549-9634(15)00187-2.

Chemical Properties

StorageStore at -20°C
M.Wt421.54
Cas No.1229582-33-5
FormulaC27H27N5
Solubility≥21.1mg/mL in DMSO
Chemical Name3-(1H-indol-5-yl)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine
SDFDownload SDF
Canonical SMILESCN1CCN(CC1)CC2=CC=C(C=C2)C3=CN=C4C(=C3)C(=CN4)C5=CC6=C(C=C5)NC=C6
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1]:

细胞系

人单核细胞

制备方法

溶解度有限。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

37℃

实验结果

URMC-099以剂量依赖性方式有效抑制TNF-α、MCP-1、IL-6和IL-8,这些物质对HIV-1相关神经认知障碍(HAND)的发病机理至关重要。与仅Tat处理相比,URMC-099对TNFα和IL-6的最低药物浓度为100 nM,而对MCP1为300 nM。

动物实验 [2]:

动物模型

Tat小鼠模型

给药剂量

注射

实验结果

在Tat暴露之前和之后使用URMC-099处理,在Tat注射位点部分保持正常Map2染色。Tat暴露显著降低注射部位的斑点密度,URMC-099将斑点密度恢复至对照水平。此外,URMC-099改变暴露于HIV-1 Tat的小胶质细胞的形态和神经元相互作用。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内

References:

1. Goodfellow VS, Loweth CJ, Ravula SB et al. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013 Oct 24;56(20):8032-48.

2. Marker DF, Tremblay M, Puccini JM et al. The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders. J Neurosci. 2013 Jun 12;33(24):9998-10010.

质量控制

化学结构

URMC-099