Ceritinib (LDK378)

For research use only.

Catalog No.S7083

60 publications

Ceritinib (LDK378) Chemical Structure

CAS No. 1032900-25-6

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 60 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)
STK22D [1]
(Cell-free assay)
FLT3 [1]
(Cell-free assay)
0.2 nM 7 nM 8 nM 23 nM 60 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) MlvaS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFfyVGE4OiCq NIHrN4ZFVVOR MljlTWM2OD1zNUi2JOKyKDF5MzDuUS=> NWDWZlBmOjV5NEmwN|Q>
WT 70 M3Lqemdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NX7X[GF7PzJiaB?= NEfkdZFFVVOR MWTJR|UxRTJzINMxJFghdk1? M3vUOFI2PzR7MEO0
G1128S 1022 NW\NTnZMT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1j6OVczKGh? M4\o[GROW09? NYi1V|NuUUN3ME2xNFIhyrFiM{igcm0> NHfje5gzPTd2OUCzOC=>
C1156F 1293 MnjiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlnoO|IhcA>? M1u4RmROW09? MmG5TWM2OD1{MUegxtEhOTF3IH7N MlXONlU4PDlyM{S=
I1171N 519 NF:ye4tIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVvPbFVMPzJiaB?= NH33d|lFVVOR MkD3TWM2OD1zOEegxtEhQDdibl2= NVziNGRkOjV5NEmwN|Q>
I1171T 445 MonQS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWXyVZdKPzJiaB?= M1jXUGROW09? NVjFNm9YUUN3ME24NkDDuSBzMjDuUS=> NHz3XmgzPTd2OUCzOC=>
F1174I 184 MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NW\nSVl{PzJiaB?= MmXpSG1UVw>? MmHjTWM2OD1zMzFCtUAxNjFibl2= M{fEVVI2PzR7MEO0
N1178H 169 MUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmTiO|IhcA>? Ml7jSG1UVw>? NGDKbXRKSzVyPUSyJOKyKDZibl2= NH7qdmozPTd2OUCzOC=>
E1210K 748 NFzNSG5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NETkOHA4OiCq NVPH[nZDTE2VTx?= M{W0b2lEPTB;MUi3JOKyKDh2IH7N M{n1VlI2PzR7MEO0
C1156F/D1203N 2809 NEO1R5RIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1TFUlczKGh? NFi5O3pFVVOR M2TEN2lEPTB;MkW0JOKyKDl7IH7N Mln4NlU4PDlyM{S=
Ba/F3 NA WT Mn6wS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3nVdFczKGh? NVXpWHVQUUN3ME2wMlAzOCEQvF2= MoHxNlU4Ojd2MEC=
Ba/F3 NA C1156Y MonTS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml63O|IhcA>? NFjmdYRKSzVyPUCuNFcyKM7:TR?= NF3GdmkzPTd{N{SwNC=>
Ba/F3 NA L1196M NWD0[WI2T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGHsNZU4OiCq MWHJR|UxRTBwMESyJO69VQ>? MVOyOVczPzRyMB?=
Ba/F3 NA L1152R NYnu[W1{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWLyXFJ[PzJiaB?= NULzUYRXUUN3ME2wMlI5QCEQvF2= MXqyOVczPzRyMB?=
Ba/F3 NA G1202R NXfUbHoxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlXVO|IhcA>? NF7x[WxKSzVyPUCuNlc4KM7:TR?= NEj2bFIzPTd{N{SwNC=>
Ba/F3 NA G1269A MlPZS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4PrdFczKGh? M3HFRWlEPTB;MD6wNVkh|ryP NILBOFMzPTd{N{SwNC=>
Ba/F3 NA S1206Y MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXK3NkBp NUTqT2dJUUN3ME2wMlA{PyEQvF2= NFv5fmIzPTd{N{SwNC=>
Ba/F3 EA WT NWjtb4NQT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlnrO|IhcA>? M{DtNmlEPTB;MD6wNlEh|ryP NHi2UI0zPTd{N{SwNC=>
Ba/F3 EA C1156Y MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2D0RVczKGh? NXe4c5p4UUN3ME2wMlAzPiEQvF2= NUnqNYNsOjV5Mke0NFA>
Ba/F3 EA L1196M NIWwTWJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NUL4UVNWPzJiaB?= NE\veoJKSzVyPUCuNFE6KM7:TR?= M4TRd|I2PzJ5NECw
Ba/F3 EA L1152R NWfZW3pnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MX63NkBp NGrSUGFKSzVyPUCuNFk6KM7:TR?= MmmzNlU4Ojd2MEC=
Ba/F3 EA G1202R M3z3T2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{W3XlczKGh? NGPRTFdKSzVyPUCuOFY4KM7:TR?= MYGyOVczPzRyMB?=
Ba/F3 EA G1269A NEjvN3VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3XMUFczKGh? NVW5enZ6UUN3ME2wMlA{OyEQvF2= MWGyOVczPzRyMB?=
Ba/F3 EA S1206Y Ml:zS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2TrfVczKGh? NHu1Z4FKSzVyPUCuNFM5KM7:TR?= Mn62NlU4Ojd2MEC=

... 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)
Ethanol 3 mg/mL (5.37 mM)
Water Insoluble

* 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 CC1=CC(=C(C=C1C2CCNCC2)OC(C)C)NC3=NC=C(C(=N3)NC4=CC=CC=C4S(=O)(=O)C(C)C)Cl

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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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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