TAE684 is a potent inhibitor of LRRK2 kinase activity (IC(50) of 7.8nM against wild-type LRRK2, 6.1nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3μM in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10mg/kg. TAE684 potently inhibits the proliferation of Ba/F3 NPM-ALK cells with IC50 of 3 nM, without affecting the survival of Ba/F3 cells even at 1 μM. TAE684 also inhibits proliferation of NPM-ALK-expressing human ALCL cell lines including Karpas-299 and SU-DHL-1 with IC50 of 2–5 nM. Molecular modeling reveals that L258 may be one of the major kinase-selectivity determinants for TAE684. TAE684 treatment results in a rapid and sustained inhibition of phosphorylation of NPM-ALK. TAE684 induces apoptosis and G1 phase arrest in NPM-ALK-expressing Ba/F3 cells and ALCL patient cell lines. be one of the major kinase-selectivity determinants for TAE684. Neurite outgrowth induced by expression of the mALK R1279Q mutant could be completely inhibited by TAE684 at 30 nM.
|Cell lines||Luciferase-expressing Karpas-299, SU-DHL-1, and Ba/F3 cells and transformed Ba/F3 stably expressing NPM-ALK, Bcr-Abl, or TEL-kinase fusion constructs.|
|Preparation method||Seeding cells in 384-well plates (2.5×104 cells per well) and incubating with serial dilutions of TAE684 or DMSO for 2–3 days. Using Luciferase expression as a measure of cell proliferation/survival and evaluating with the Bright-Glo Luciferase Assay System.Using XLFit software to generate IC50 values .|
|Concentrations||1 nM-10 μM|
|Incubation time||2–3 days|
|Animal models||Karpas-299 xenografts are established in 4- to 6-week old female Fox Chase SCIDBeige mice|
|Formulation||Resuspended in 10% 1-methyl-2-pyrrolidinone/90% polyethylene glycol 300 solution|
|Dosages||1, 3, and 10 mg/kg|
|Administration||Once daily by oral gavage for 3 weeks|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥28 mg/mL
Ethanol ≥1.8 mg/mL
Characterization of TAE684 as a potent LRRK2 kinase inhibitor.
Zhang J, et al. Bioorg Med Chem Lett. 2012 Mar 1;22(5):1864-9. PMID: 22335897.
Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684.
Schönherr C, et al. Biochem J. 2011 Dec 15;440(3):405-13. PMID: 21838707.
Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.
Galkin AV, et al. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. PMID: 17185414.
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