Ceritinib (LDK378)

For research use only.

Catalog No.S7083

52 publications

Ceritinib (LDK378) Chemical Structure

Molecular Weight(MW): 558.14

Ceritinib (LDK378) is potent inhibitor against ALK with IC50 of 0.2 nM in cell-free assays. Ceritinib (LDK378) also inhibits IGF-1R, InsR, STK22D and FLT3 with IC50 of 8 nM, 7 nM, 23 nM and 60 nM, respectively. Phase 3.

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Selleck's Ceritinib (LDK378) has been cited by 52 publications

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Biological Activity

Description Ceritinib (LDK378) is potent inhibitor against ALK with IC50 of 0.2 nM in cell-free assays. Ceritinib (LDK378) also inhibits IGF-1R, InsR, STK22D and FLT3 with IC50 of 8 nM, 7 nM, 23 nM and 60 nM, respectively. Phase 3.
Features Does not cross react with c-Met, and has an improved in vivo glucose homeostasis profile relative to TAE684. May be active in Crizotinib-relapsed tumors.
Targets
ALK [1]
(Cell-free assay)
Insulin Receptor [1]
(Cell-free assay)
IGF-1R [1]
(Cell-free assay)
0.2 nM 7 nM 8 nM
In vitro

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. [1]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Parental(+IL3) NHvCeJlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVTPZWxbPzJiaB?= Mle0SG1UVw>? MXnJR|UxRTF3OE[gxtEhOTd|IH7N M2Lqe|I2PzR7MEO0
WT 70 MWPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVm3NkBp NWPGeJR6TE2VTx?= MWPJR|UxRTJzINMxJFghdk1? MnTHNlU4PDlyM{S=
G1128S 1022 MoXkS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{juW|czKGh? NH70R5NFVVOR MYrJR|UxRTFyMjFCtUA{QCCwTR?= NXqyfHFUOjV5NEmwN|Q>
C1156F 1293 M3jpc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4X5[VczKGh? Mn7ISG1UVw>? NGXU[5NKSzVyPUKxO{DDuSBzMUWgcm0> M33SUFI2PzR7MEO0
I1171N 519 MU\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXu3NkBp NHfXbI9FVVOR M{[zU2lEPTB;MUi3JOKyKDh5IH7N NIrJV3EzPTd2OUCzOC=>
I1171T 445 NFjaUXhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2HH[|czKGh? MUjEUXNQ MmPBTWM2OD16MjFCtUAyOiCwTR?= NYHOcplFOjV5NEmwN|Q>
F1174I 184 NWnzRlN5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnP4O|IhcA>? NHzHS2JFVVOR M17UTmlEPTB;MUOgxtEhOC5zIH7N M4[3fVI2PzR7MEO0
N1178H 169 NHP6boxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXK3NkBp M2DsNGROW09? NIDMdFNKSzVyPUSyJOKyKDZibl2= Ml;sNlU4PDlyM{S=
E1210K 748 MYjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3\XS|czKGh? MoL3SG1UVw>? MWrJR|UxRTF6NzFCtUA5PCCwTR?= M2O0d|I2PzR7MEO0
C1156F/D1203N 2809 NGfKTllIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGH2Z3k4OiCq NWrkOoR5TE2VTx?= M{npeGlEPTB;MkW0JOKyKDl7IH7N M1PCb|I2PzR7MEO0
Ba/F3 NA WT NXrQR3l4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MoSwO|IhcA>? M13hUGlEPTB;MD6wNlAh|ryP MmHkNlU4Ojd2MEC=
Ba/F3 NA C1156Y NVuxdYpDT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NF7mfJA4OiCq M1TafGlEPTB;MD6wO|Eh|ryP M1TscFI2PzJ5NECw
Ba/F3 NA L1196M M3i3eGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmjhO|IhcA>? M1HlVWlEPTB;MD6wOFIh|ryP M2HhbFI2PzJ5NECw
Ba/F3 NA L1152R MXfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFf1Voc4OiCq M3O3dWlEPTB;MD6yPFgh|ryP M1ThXVI2PzJ5NECw
Ba/F3 NA G1202R M1;MTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MX:3NkBp M1SwWWlEPTB;MD6yO|ch|ryP MXWyOVczPzRyMB?=
Ba/F3 NA G1269A NIP0dJZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Mmf0O|IhcA>? MkLLTWM2OD1yLkCxPUDPxE1? NELW[pEzPTd{N{SwNC=>
Ba/F3 NA S1206Y M{DEdWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NGTiRpA4OiCq NUjNOHdqUUN3ME2wMlA{PyEQvF2= MX2yOVczPzRyMB?=
Ba/F3 EA WT M1X1NGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3fNV|czKGh? MoH6TWM2OD1yLkCyNUDPxE1? MWeyOVczPzRyMB?=
Ba/F3 EA C1156Y MXPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX3LR49[PzJiaB?= NXHEUHhFUUN3ME2wMlAzPiEQvF2= MWSyOVczPzRyMB?=
Ba/F3 EA L1196M NVzKToFCT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mn33O|IhcA>? NEn6N3NKSzVyPUCuNFE6KM7:TR?= MnvPNlU4Ojd2MEC=
Ba/F3 EA L1152R M3fndmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmTuO|IhcA>? M3rXPGlEPTB;MD6wPVkh|ryP M3riN|I2PzJ5NECw
Ba/F3 EA G1202R MYrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoT5O|IhcA>? M3XRNWlEPTB;MD60Olch|ryP NWP2VlNvOjV5Mke0NFA>
Ba/F3 EA G1269A NWLvWHcyT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYe3NkBp MonITWM2OD1yLkCzN{DPxE1? MmPGNlU4Ojd2MEC=
Ba/F3 EA S1206Y NWDnblllT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MX[3NkBp NY\uVpY3UUN3ME2wMlA{QCEQvF2= MnexNlU4Ojd2MEC=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-ALK / ALK / p-AKT / AKT / p-ERK / ERK; 

PubMed: 28425916     


Inhibition of ALK autophosphorylation and downstream signaling by ceritinib, crizotinib and PF06463922 in NB-1 cells. Cells were harvested after treatment for 4 hr with the indicated compounds at different concentrations. Whole cell lysates were analyzed by Western blotting to detect the levels of ALK, AKT and ERK proteins and their phosphorylation.

pROS1 / ROS1 / pSTAT3 / STAT3 ; 

PubMed: 25351743     


Inhibition of phospho-ROS1 by various ALK inhibitors in Ba/F3 models. CD74-ROS1 expressing Ba/F3 cells were exposed to increasing concentrations of crizotinib, ceritinib, AP26113, or ASP3026 for 3 h. Cell lysates were immunoblotted to detect the indicated proteins.

28425916 25351743
Growth inhibition assay
Cell viability; 

PubMed: 29067644     


The effects of ceritinib treatment on cell viability in ARMS and ERMS cell lines. Cells were treated with 0-5 μM ceritinib for 72 h (Rh30, RD), 120 h (Rh41), or 144 h (Rh18, Aska) and cell viability was assessed. The y-axis represents relative cell viability compared to non-treated cells (control). Effects on cell viability were determined in triplicate. Values are presented as mean ± SD. Dotted line represents the IC50-value. The human synovial sarcoma cell line Aska with constitutive ALK phosphorylation was used as a positive control.

29067644
In vivo LDK378 is designed to reduce the possibility of forming reactive metabolites and shows undetectable levels of glutathione (GSH) adducts (<1%) in liver microsomes. LDK378 has relatively good metabolic stability, with moderate CYP3A4 (Midazolam substrate) inhibition and hERG inhibition. LDK378 exhibits low plasma clearance in animals (mouse, rat, dog and monkey) compared to liver blood flow, with the oral bioavailability of above 55% in mouse, rat, dog and monkey. LDK378 induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. LDK378 shows no impact on insulin levels or plasma glucose utilization in the mouse upon chronic dosing up to 100 mg/kg. [1]

Protocol

Kinase Assay:[1]
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Enzymatic kinase profiling description:

All kinases are expressed as either Histidine- or GST-tagged fusion proteins using the baculovirus expression technology except for the untagged ERK2 which is produced in E. coli. The kinase activity is measured in the LabChip mobility shift assay. The assay is performed at 30°C for 60 min. The effect of LDK378 on the enzymatic activity is obtained from the linear progress curves in the absence and presence of LDK378 and routinely determines from one reading (end point measurement)
Cell Research:[1]
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  • Cell lines: Ba/F3-NPM-ALK, Ba/F3-Tel-InsR, Ba/F3-WT, Karpas299 cells
  • Concentrations: ~100 μM
  • Incubation Time: 2-3 days
  • 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.
    (Only for Reference)
Animal Research:[1]
- Collapse
  • Animal Models: RNU nude rats bearing the Karpas299/H2228 tumors
  • Dosages: ~50 mg/kg
  • Administration: Oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 20 mg/mL warmed (35.83 mM)
Water Insoluble
Ethanol '3 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 558.14
Formula

C28H36ClN5O3S

CAS No. 1032900-25-6
Storage powder
in solvent
Synonyms N/A
Smiles CC(C)OC1=C(NC2=NC(=C(Cl)C=N2)NC3=C(C=CC=C3)[S](=O)(=O)C(C)C)C=C(C)C(=C1)C4CCNCC4

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02450903 Completed Drug: LDK378 Non-Small-Cell Lung Cancer Novartis Pharmaceuticals|Novartis August 21 2015 Phase 2
NCT02276027 Completed Drug: BYL719|Drug: INC280|Drug: LDK378|Drug: MEK162 Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma Novartis Pharmaceuticals|Novartis January 20 2015 Phase 2
NCT02040870 Completed Drug: LDK378 Non-Small Cell Lung Cancer Novartis Pharmaceuticals|Novartis March 7 2014 Phase 1|Phase 2
NCT01950481 Completed Drug: LDK378 Normal Hepatic Function|Impaired Hepatic Function Novartis Pharmaceuticals|Novartis January 2014 Phase 1
NCT01772797 Completed Drug: LDK378|Drug: AUY922 Anaplastic Lymphoma Kinase (ALK)|Non-small Cell Lung Cancer Novartis Pharmaceuticals|Novartis June 2013 Phase 1
NCT01685060 Completed Drug: LDK378 Non-Small Cell Lung Cancer Novartis Pharmaceuticals|Novartis November 26 2012 Phase 2

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

  • Question 1:

    how to reconstitute the inhibitor for oral administration to mice?

  • Answer:

    You can resuspend LDK378 in 30% PEG400/0.5% Tween 80/5% propylene glycol and use the suspension for oral gavage feeding.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID