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GNE-3511

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Chemical Structure| 1496581-76-0 同义名 : -
CAS号 : 1496581-76-0
货号 : A822343
分子式 : C23H26F2N6O
纯度 : 99%+
分子量 : 440.489
MDL号 : MFCD28502215
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 30 mg/mL(68.11 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
描述 DLK (dual leucine zipper kinase, MAP3K12) is identified as an essential regulator of neuronal degeneration in multiple contexts, as loss of DLK expression resulted in protection of retinal ganglion cell neurons from degeneration as well as an attenuation of downstream signaling, following injury. GNE-3511 is a potent, selective and brain-penetrant DLK inhibitor with Ki value less than 0.5nM. Suppression of DLK through GNE-3511 led to inhibition of p-JNK and primary rat dorsal root ganglion (DRG) neurons in an in vitro axon degeneration assay with IC50 values of 30nM and 107nM, respectively. GNE-3511 exhibited very good selectivity over the other JNK pathway kinases and homologues of DLK, with IC50 values of 129, 514, 364, 67.8, 767 and 602nM for JNK1, 2, 3, MLK1, 2, 3, respectively, as well as >5000nM for both MKK4 and 7. Oral administration of GNE-3511 30min prior to nerve crush injury dose-dependently reduced p-c-Jun level induced by injury, as a pharmacodynamics readout of DLK inhibition in vivo, in retina of a Nerve Crush model at dose of 25mg/kg and 75mg/kg, and in dopaminergic neurons of the substantia nigra in a MPTP-induced Parkinson’s disease model at dose of 37.5 and 75mg/kg.
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.27mL

0.45mL

0.23mL

11.35mL

2.27mL

1.14mL

22.70mL

4.54mL

2.27mL
参考文献

[1]Musich T, Demberg T, et al. Purification and functional characterization of mucosal IgA from vaccinated and SIV-infected rhesus macaques. Clin Immunol. 2015 Jun;158(2):127-39.

[2]Patel S, Cohen F, et al. Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J Med Chem. 2015 Jan 8;58(1):401-18.