LDK378 是一种选择性，具有口服活性的、ATP 竞争性的ALK酪氨酸激酶抑制剂，IC50=200 pM。 它还抑制IGF-1R (IC50:8 nM)，InsR (IC50:7 nM) 和 STK22D (IC50:23 nM)。它显示出良好抗肿瘤效力。

Ceritinib (LDK378) is a specific ALK inhibitor (IC50: 0.2 nM).

Ceritinib (LDK378) also inhibits RET (IC50: 400 nM), FGFR3 (IC50: 430 nM), LCK (IC50: 560 nM), JAK2 (IC50: 610 nM), Aurora (IC50: 660 nM), LYN (IC50: 840 nM), EGFR (IC50: 900 nM), and FGFR4 (IC50: 950 nM) [1]. In ALK-positive cell line models, ceritinib was able to effectively inhibit ALK harboring the crizotinib-resistant mutations L1196M, G1269A, I1171T, and S1206Y, but it was ineffective at inhibiting ALK containing the G1202R and F1174C mutations.49 Among a panel of 46 other tested kinases, ceritinib showed strong activity only against IGF-1R (IC50: 8 nM), INSR (IC50: 7 nM), and STK22D (IC50: 23 nM) [2].

Mice treated with ceritinib at 50 mg/kg remained in complete remission with no discernible tumor growth for 4 months. In the mice treated with ceritinib at 25 mg/kg, tumor re-growth was observed in 4 out of 8 animals after 1 month, whereas complete remission was maintained in the other 4 animals for 4 months. In a primary explant model derived from a crizotinib-na?ve NSCLC tumor MGH006, treatment with 25 mg/kg ceritinib also led to tumor regressions [3].

All kinases were expressed as either Histidine- or GST-tagged fusion proteins using the baculovirus expression technology except for the untagged ERK2 which was produced in E. coli. The kinase activity was measured in the LabChip mobility-shift assay. The assay was performed at 30°C for 60 min. The effect of the compound on the enzymatic activity was obtained from the linear progress curves in the absence and presence of compound and routinely determined from one reading (end point measurement) [1].

Luciferase-expressing cells were incubated with serial dilutions of compounds or DMSO for 2–3 days. Luciferase expression was used as a measure of cell proliferation/survival and was evaluated with the Bright-Glo Luciferase Assay System. IC50 values were generated by using XLFit software [1].

SCID beige mice for crizotinib-resistant H2228 xenograft tumor models, nude mice for MGH006 primary explants and MGH045 cells were randomized into groups of 5, 6 or 8 mice with an average tumor volume of ~150 mm^3 and received Crizotinib or ceritinib daily treatments by oral gavage as indicated in each study. Tumor volumes were determined by using caliper measurements and calculated with the formula (Length × Width × Height)/2 [3].

1032900-25-6

C28H36ClN5O3S

558.14

LDK378;色瑞替尼

Ethanol:3 mg/mL (5.37 mM)
DMSO:16 mg/mL (28.7 mM)
H2O:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years