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CAS No.: 1285515-21-0

GSK2578215A Catalog No. CSN15754

Synonyms: GSK2578215A

GSK2578215A is a brain-penetrant, potent and selective LRRK2 inhibitor with IC50 values of 8.9 and 10.1 nM for LRRK2[G2019S] mutant and wild-type LRRK2, respectively.

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 LRRK2

IC50:10.9nM LRRK2 (G2019S)

IC50:8.9nM
描述Leucine-rich repeat kinase 2 (LRRK2)-dependent signaling pathway is associated with familial and sporadic Parkinson's disease. GSK2578215A is a potent, highly selective LRRK2 kinase inhibitor with IC50 values of 10.9 nM and 8.9 nM against wild-type LRRK2 and mutant LRRK2, respectively. GSK2578215A (0.01 – 1 μM, 90min incubation) dose-dependently inhibited the phosphorylation of Ser910 and Ser935 in HEK293 cells stably expressing wild-type LRRK2 and mutant LRRK2. Similarly, in human lymphoblastoid cells derived from Parkinson's disease patient homozygous, GSK2578215A (0.01 – 1 μM, 90min incubation) resulted in the dephosphorylation of endogenous LRRK2 at Ser910 and Ser935^[3]. In SH-SY5Y cells transfected with GFP-LC3 vector, 12h treatment with 1nM GSK2578215A significantly increased the protein levels of endogenous LC3 and p62 compared to the control cells. In addition, GSK2578215A also increased the number of autophagosomes per cell and induced the accumulation of 4-HNE in SH-SY5Y cells 12h after the treatment^[4]. In vivo, intraperitoneal injection of GSK2578215A (100 mg/kg) to wild-type mice caused complete dephosphorylation of LRRK2 Ser910 and Ser935 in kidney and spleen, whereas no inhibition of LRRK2 Ser910 or Ser935 phosphorylation was found in the brain^[3].
作用机制GSK2578215A is a potent, selective cellular inhibitor of LRRK2 kinase activity that binds at the hinge of the ATP site of LRRK2, inducing significant inhibition against wild-type and mutant LRRK2 both in vitro and in vivo^[3].

动物研究

剂量

Mice: 1 mg/kg^[2] (i.v.); 10 mg/kg^[2] (p.o.); 100 mg/kg^[2] (i.p.)

给药途径

i.v., p.o., i.p.

动物药代数据

Animal	Mice^[2]
Dose	1 mg/kg (i.v.) 10 mg/kg (p.o.)
Administration	i.v. p.o.
F	12.2% (i.v.)
T_1/2	1.14 h (i.v.)
AUC_last	519.6 h·ng/ml (i.v.) 635.3 h·ng/ml (p.o.)
CL	30.0 ml/min/kg (i.v.)
Vss	2.3 L/kg (i.v.)
Brain: plasma	1.4 (i.v.) 2.4 (p.o.)

参考文献

[1] Saez-Atienzar S, Bonet-Ponce L, et al. The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling. Cell Death Dis. 2014 Aug 14;5:e1368.
[2] Reith AD, Bamborough P, et al. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg Med Chem Lett. 2012 Sep 1;22(17):5625-9.
[3] Reith AD, Bamborough P, Jandu K, Andreotti D, Mensah L, Dossang P, Choi HG, Deng X, Zhang J, Alessi DR, Gray NS. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg Med Chem Lett. 2012 Sep 1;22(17):5625-9.
[4] Saez-Atienzar S, Bonet-Ponce L, Blesa JR, Romero FJ, Murphy MP, Jordan J, Galindo MF. The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling. Cell Death Dis. 2014 Aug 14;5(8):e1368.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.5036 mL
- 12.5182 mL
- 25.0365 mL
- 5 mM
- 0.5007 mL
- 2.5036 mL
- 5.0073 mL
- 10 mM
- 0.2504 mL
- 1.2518 mL
- 2.5036 mL

技术信息

CAS号

1285515-21-0

储存条件

粉末: Inert atmosphere,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C24H18FN3O2

运输

蓝冰

分子量

399.42

别名

GSK2578215A

溶解度

DMSO	77.0 mg/mL (192.8 mM) warming
Water	Insoluble
Ethanol	Insoluble

动物实验配方

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靶点	Description	IC50
LRRK2		IC50:10.9nM
LRRK2 (G2019S)		IC50:8.9nM

GSK2578215A Catalog No. CSN15754

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