LDK378 is a selective small molecule inhibitor of ALK, a target found in metastatic non-small cell lung cancer (NSCLC). LDK378 shows great anti-proliferative activity in Ba/F3-NPM-ALK and Karpas290 cells with IC50 of 26.0 nM and 22.8 nM, compared with IC50 of 319.5 nM and 2477 nM in Ba/F3-Tel-InsR and Ba/F3-WT cells. LDK378 induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. In Phase I trials, LDK378 showed a marked clinical response in 78 patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer who had progressed during or after crizotinib therapy or had not been previously treated with crizotinib.
Med Oncol. 2022 Dec 28;40(1):64.
FAT4 activation inhibits epithelial-mesenchymal transition (EMT) by promoting autophagy in H2228/Cer cells
LDK378 purchased from AbMole
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Source | Oncotarget (2015). Figure 2. LDK378 |
| Method | p.o. | |
| Cell Lines | nude mice | |
| Concentrations | 25 mg/kg | |
| Incubation Time | 21 day | |
| Results | There was a significant inhibition of tumor growth in the group with a combination of ceritinib and paclitaxel compared with other groups (P < 0.05) |
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Source | Oncotarget (2015). Figure 1. LDK378 |
| Method | MTT assay | |
| Cell Lines | HEK293/ABCB1 and HEK293/ABCG2-R2 cells | |
| Concentrations | 0.5 μM | |
| Incubation Time | 48 h | |
| Results | Based on the cytotoxicity curves, more than 85% of the cells survived at the concentration of 0.5 μM ceritinib |
| Cell Experiment | |
|---|---|
| Cell lines | Ba/F3-NPM-ALK, Ba/F3-Tel-InsR, Ba/F3-WT, Karpas299 cells |
| Preparation method | Luciferase-expressing cells are incubated with serial dilutions of LDK378 or DMSO for 2-3 days. Luciferase expression is used as a measure of cell proliferation/survival and is evaluated with the Bright-Glo Luciferase Assay System. IC50 values are generated by using XLFit software. |
| Concentrations | ~100 μM |
| Incubation time | 2-3 days |
| Animal Experiment | |
|---|---|
| Animal models | RNU nude rats bearing the Karpas299/H2228 tumors |
| Formulation | LDK378 (phosphate salt) formulated in 0.5% methylcellulose/0.5% Tween 80 |
| Dosages | ~50 mg/kg |
| Administration | Oral gavage |
| Molecular Weight | 558.14 |
| Formula | C28H36ClN5O3S |
| CAS Number | 1032900-25-6 |
| Solubility (25°C) | DMSO 10 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.
| Related ALK Products |
|---|
| NVL-655
NVL-655 is a novel, brain-permeable, selective ALK inhibitor with antitumor activity. For Ba/F3 CLIP1-LTK cells, NVL-655 has an IC50 of 2.7 nM. It can be used in studies related to ALK-positive non-small cell lung cancer (NSCLC). |
| APG-2449
APG-2449 is an orally active, potent ALK/ROS1/FAK inhibitor with anti-tumor activity in a mouse model of non-small cell lung cancer (NSCLC). |
| ALK2-IN-5
ALK2-IN-5, pyrazolopyrimidine compound, is an ALK2 inhibitor. |
| J-1048
J-1048 is an activin receptor-like kinase 5 (ALK5) inhibitor. |
| CPD-1224
CPD-1224 is an orally active derivative of ALK inhibitors to cereblon ligands. |
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