LRRK2-IN-1
分子式:C₃₁H₃₈N₈O₃分子量:570.69
简介 :LRRK2-IN-1 是一种有效的,选择性的 LRRK2 抑制剂,作用于 LRRK2 (G2019S) 和 LRRK2 (WT),IC50 值分别为 6 nM 和 13 nM。
物理性状及指标:
外观:……………………粉末
溶解性:…………………DMSO : ≥ 50 mg/mL (87.61 mM)
含量:……………………>98%,BR
储存条件:-20°C,避光防潮密闭干燥
运输条件:2~8℃运输
生物活性
描述
|
LRRK2-IN-1 is a potent and selective LRRK2 inhibitor with IC50 of 6 nM and 13 nM for LRRK2 (G2019S) and LRRK2 (WT), respectively. |
IC50 & Target |
IC50: 13 nM (WT), 6 nM (G2019S) |
体外 |
Wild-type and G2019S transduction results in 2.5 fold higher TR-FRET signal which can be inhibited by LRRK2-IN-1 in a dose-dependent manner with IC50 values of 0.08 µM and 0.03 µM, respectively. LRRK2-IN-1 possessed an IC50 of 45 nM for inhibition of DCLK2 and exhibits an IC50 of greater than 1 µM when evaluated in biochemical assays for AURKB, CHEK2, MKNK2, MYLK, NUAK1, and PLK1. LRRK2-IN-1 is confirmed to inhibit MAPK7 with an EC50 of 160 nM. LRRK2-IN-1 induces a dose dependent inhibition of Ser910 and Ser935 phosphorylation accompanied by loss of 14-3-3 binding to both wild type LRRK2 and LRRK2[G2019S] stably transfected into HEK293 cells. LRRK2-IN-1 is moderately cytotoxic with IC50 of 49.3 µM in HepG2 cells. LRRK2-IN-1 exhibits genotoxicity in the presence and absence of S9 at 15.6 and 3.9 µM, respectively. LRRK2-IN-1 inhibits proliferation, migration, and induces cell death with hallmarks of apoptosis of HCT116 and AsPC-1 cells. |
体内 |
LRRK2-IN-1 (100 mg/kg, i.p.) induces dephosphorylation of LRRK2 in the kidney of the mice. Peritumoral injection of LRRK2-IN-1 (100 mg/kg) results in a significant decrease in tumor volume and weight of AsPC-1 tumor xenografts. |
实验参考方法(仅来自公开文献,供参考)
Kinase Assay |
Active GST-LRRK2 (1326-2527), GST-LRRK2 [G2019S] (1326-2527), GST-LRRK2 [A2016T] (1326-2527) and GST-LRRK2 [A2016T+G2019S] (1326-2527) enzyme is purified with glutathione sepharose from HEK293 cell lysate 36 h following transient transfection of the appropriate cDNA constructs. Peptide kinase assays, performed in duplicate, are set up in a total volume of 40 µL containing 0.5 µg LRRK2 kinase (which at approximately 10% purity gives a final concentration of 8 nM) in 50 mM Tris/HCl, pH 7.5, 0.1 mM EGTA, 10 mM MgCl2, 20 µM Nictide, 0.1 µM [γ-32P]ATP (500 cpm/pmol) and the indicated concentrations of inhibitor dissolved in DMSO. After incubation for 15 min at 30°C, reactions are terminated by spotting 35 µL of the reaction mix onto P81 phosphocellulose paper and immersion in 50 mM phosphoric acid. Samples are washed extensively and the incorporation of [γ-32P]ATP into Nictide is quantified by Cerenkov counting. IC50 values are calculated with GraphPad Prism using non-linear regression analysis. |
细胞实验: |
Cells (104 cells per well) are seeded into a 96-well tissue culture plate in triplicate. The cells are cultured in the presence of LRRK2-IN-1 with DMSO as a vehicle at 0, 0.31, 0.63, 1, 2, and 5, 10, and 20 μM. 48 h post treatment, 10 μL of TACS MTT Reagent is added to each well and the cells are incubated at 37°C until dark crystalline precipitate become visible in the cells. 100 μL of 266 mM NH4OH in DMSO is then added to the wells and placed on a plate shaker at low speed for 1 minute. After shaking, the plate is allowed to incubate for 10 minutes protected from light and the OD550 for each well is read using a microplate reader. The results are averaged and calculated as a percentage of the DMSO (vehicle) control +/- the standard error of the mean. |
动物实验 |
LRRK2-IN-1 is dissolved in Captisol and administered by intraperitoneal injection into wild type male C57BL/6 mice at a dose of 100 mg/kg. Control mice are injected with an equal volume of Captisol. At 1 and 2 h time points, mice are extinguwashed by cervical dislocation and kidney and brain tissue rapidly dissected and snap-frozen in liquid nitrogen. |
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储液配置及储存: 按表中溶解性配置;如溶解困难,可以通过快速搅拌,超声或温和加热(在45-60°C下水浴)。液体稳定性报道的很少,建议现配现用,如需储存,建议:-20℃1-3月;-80℃ 3-6月。
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1 mg |
5 mg |
10 mg |
1 mM |
1.7523 mL |
8.7613 mL |
17.5226 mL |
5 mM |
0.3505 mL |
1.7523 mL |
3.5045 mL |
10 mM |
0.1752 mL |
0.8761 mL |
1.7523 mL |
【注意 】
●我司产品为非无菌包装,若用于细胞培养,请提前做预处理,除去热原细菌,否则会导致染菌。
●部分产品我司仅能提供部分信息,我司不保证所提供信息的权威性,以上数据仅供参考交流研究之用。
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