產品描述: | CZC-25146 is a potent and orally active LRRK2 inhibitor with IC50 values of 4.76 nM and 6.87 nM for wild-type LRRK2 and G2019S LRRK2, respectively. CZC-25146 inhibits PLK4, GAK, TNK1, CAMKK2 and PIP4K2C as well. CZC-25146 prevents mutant LRRK2-induced injury of neurons in vitro. CZC-25146 exhibits relatively favorable pharmacokinetic properties in mice. CZC-25146 can increase normal α-1-antitrypsin (AAT) secretion and reduce inflammatory cytokines. CZC-25146 can be used to research Parkinson's disease and liver diseases |
靶點: |
IC50: 4.76 nM (wild-type LRRK2), 6.87 nM (G2019S LRRK2);LRRK2 |
體外研究: |
CZC-25146 (0.01-5 μM; 7 days) does not cause cytotoxicity in human cortical neurons, nor blocking neuronal development. CZC-25146 (0.01-5 μM; 2 days) potently attenuates G2019S LRRK2-mediated toxicity in primary rodent neurons in a concentration-dependent manner with an EC50 of ~100 nM. CZC-25146 (0.06-1000 nM) rescues LRRK2 G2019S-induced neurite defects in primary human neurons in a dose-dependent manner. CZC-25146 (14.3 and 28.6 μM; 48 h) markedly reduces The mutant AAT encoded by the Z allele (ATZ) polymer load and restores AAT secretion in iPSC-Hepatocyte, without compromising cell viability. Cell Cytotoxicity Assay Cell Line: Human cortical neurons Concentration: 0.01, 0.1, 1 and 5 μM Incubation Time: 7 days Result: Did not cause cytotoxicity in human cortical neurons at concentrations below 5 μM over a seven-day treatment in culture, nor did it block neuronal development. |
體內研究: |
CZC-25146 (250 mg/kg; p.o.; 14 days) reduces the ATZ polymer levels in over expressing human polymeric ATZ mice. CZC-25146 (1 mg/kg for i.v.; 5 mg/kg for p.o.; single dosage) exhibits relatively good pharmacokinetic properties and an extensive distribution throughout animal body following intravenous injection into mice. Animal Model: Genetically modified male mice (6 weeks; over expressing human polymeric ATZ) Dosage: 250 mg/kg Administration: p.o.; 14 days Result: Dramatically and reproducibly reduced the ATZ polymer levels with an overall reduction from 60% in the control group to 37%. |
參考文獻: |
1. Ramsden N, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem Biol. 2011 Oct 21;6(10):1021-8. 2. Atashrazm F, et al. LRRK2 inhibitors and their potential in the treatment of Parkinson's disease: current perspectives. Clin Pharmacol. 2016 Oct 20;8:177-189. 3. Deniz Kent, et al. Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency. |
溶解性: |
soluble in DMSO |
保存條件: |
-20℃ |
配置溶液濃度參考: |
|
1mg |
5mg |
10mg |
1 mM |
2.047 ml |
10.235 ml |
20.469 ml |
5 mM |
0.409 ml |
2.047 ml |
4.094 ml |
10 mM |
0.205 ml |
1.023 ml |
2.047 ml |
50 mM |
0.041 ml |
0.205 ml |
0.409 ml |
|
注意: |
部分產品我司僅能提供部分信息,我司不保證所提供信息的權威性,僅供客戶參考交流研究之用。 |