Cell lines

The murine pro-B cell line Ba/F3, human cell line Karpas290

Preparation method

The solubility of this compound in DMSO is >14mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

10 to 50 nM

Applications

LDK378 showed great anti-proliferative activity in Ba/F3-NPM-ALK and Karpas290 cells.

Animal models

2-week Karpas299 (sc injection of Karpas299 cells possessing the NPM-ALK fusion) and H2228 (sc injection of H2228 cells possessing the EML4-ALK fusion) rat xenograft models

Dosage form

6.25, 12.5, 25, 50 mg/kg; every day for 14 consecutive days

Application

In the Karpas299 study, LDK378 induced a dose-dependent growth inhibition and tumor regression. In the H2228 study, LDK378 induced a dose-dependent growth inhibition and complete tumor regression at 25mg/kg. In both models, LDK378 was well tolerated and no body weight loss was observed at all doses tested.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

LDK378 is a highly potent inhibitor of anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase belonging to the superfamily of insulin receptor, with half maximal inhibitory concentration IC50 of 200 pM. LDK378 also exhibits modest to high inhibition against a panel of other kinases, in which only three kinases with IC50 below 100 nM includes IGF-1R (8 nM), InsR (7 nM) and STK22D (23 nM). In previous studies, LDK378 has been found to inhibit the proliferation of Ba/F3 cells transfected with the NPM-ALK fusion gene and Karpas 299 human non-Hodgkin’s Ki-positivr large cell lymphoma harboring the NPM-ALK fusion gene with IC50 of 22.8 nM and 26 nM.

References:
[1]Chen J, Jiang C, Wang S. LDK378: a promising anaplastic lymphoma kinase (ALK) inhibitor. J Med Chem. 2013 Jul 25;56(14):5673-4. doi: 10.1021/jm401005u. Epub 2013 Jul 9.
[2]Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26.