生物活性

• 靶点

  GSK-3α IC50:1.5nM

  GSK-3β IC50:0.9nM

• 描述GSK-3 (Glycogen synthase kinase 3) is a serine/threonine protein kinase, consisting of GSK-3a and b subunit, which plays a key role in many different biological processes including tumorigenesis, cell survival and developmental patterning. GSK-3 is constitutively active in non-stimulated cells and can negatively regulate canonical Wnt/b-catenin signaling^[1]. LY2090314 is a potent inhibitor of GSK-3 with IC50 values of 1.5 nM and 0.9 nM for GSK3a and GSKb (measured by enzyme activity of human recombinant GSK3), respectively. LY2090314 can activate the Wnt pathway in melanoma cell lines. Exposure of LY2090314 activated in a dose dependent manner in the TCF/LEF luminescent reporter in A375 cells following 5 hours. Treatment with 20 nM LY2090314 promoted a time-dependent stabilization of β-catenin total protein as well as an induction of Axin2, accompanied with inhibition of GSK3 phosphorylation at tyrosine 279 and β-catenin at serine 33/37 and threonine 41. LY2090314 (IC50 <0.05 μM) can potently induce apoptotic cell death in a range of melanoma cell lines and increase the level of activated caspase as well as cleaved PARP in A375, M14 and Mel1102 cells on dose of 15-40 nM^[2]. Treatment with 15 - 30 μM LY2090314 led to dose-dependent enhancement of NK cell activity against an AML cell line, OCI-AML3 and primary AML patient samples^[3].
• 作用机制LY2090314 is a small molecule bisarylmaleimide, which is identified as potent ATP-competitive GSK-3 inhibitor^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human SY5Y cells	-	Function assay	-	Inhibition of Glycogen synthase kinase-3 beta dependent Tau protein serine-396 phosphorylation in human SY5Y cells, IC50=0.7 nM	15267232

• 动物研究
  剂量	Mice[2] (i.v.): min = 2.5 mg/kg, max = 25 mg/kg
  给药途径	i.v.
  动物药代数据	Animal Rats[4] Dogs[4] Dose 5 mg/kg 5 mg/kg Administration i.v. i.v. Cmax 1680 ng/ml 5090 ± 2709 ng/ml T1/2 0.358 h 0.662 ± 0.145 h AUC0→∞ 1260 ng·h/ml 3227 ± 1060 ng·h/ml CL 3450 ml/h/kg 1673 ± 540 ml/h/kg Tmax 0.5 h 0.5 ± 0.0 h Vdss 1189 ml/kg 915 ± 415 ml/kg

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01214603	Leukemia	Phase 2	Completed	-	United States, Illinois ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Chicago, Illinois, United States, 60637 United States, Minnesota For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Minneapolis, Minnesota, United States, 55455 United States, North Carolina For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Durham, North Carolina, United States, 27710 United States, Texas For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Houston, Texas, United States, 77030 Collapse <<
  NCT01287520	Advanced Cancer	Phase 1	Completed	-	United States, Florida ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tampa, Florida, United States United States, Tennessee For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nashville, Tennessee, United States Collapse <<
  NCT01632306	-	-	Terminated(Study has been term... more >>inated due to slow enrollment.) Collapse <<	-	-

• 更多
• 参考文献

• [1] Domoto T, Pyko IV, et al. Glycogen synthase kinase-3β is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci. 2016 Oct;107(10):1363-1372.

  [2] Atkinson JM, Rank KB, et al. Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3. PLoS One. 2015 Apr 27;10(4):e0125028.

  [3] Martinez A, Castro A, et al. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev. 2002 Jul;22(4):373-84.

  [4] Zamek-Gliszczynski MJ, Abraham TL, et al. Pharmacokinetics, metabolism, and excretion of the glycogen synthase kinase-3 inhibitor LY2090314 in rats, dogs, and humans: a case study in rapid clearance by extensive metabolism with low circulating metabolite exposure. Drug Metab Dispos. 2013 Apr;41(4):714-26.