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 Experiment | |
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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 Experiment | |
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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 |
Molecular Weight | 614.2 |
Formula | C30H40ClN7O3S |
CAS Number | 761439-42-3 |
Solubility (25°C) | DMSO ≥28 mg/mL Ethanol ≥1.8 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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