Ceritinib (LDK378)

Catalog No.S7083

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, shows 40- and 35-fold selectivity against IGF-1R and InsR, respectively. Phase 3.

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Cited by 33 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, shows 40- and 35-fold selectivity against IGF-1R and InsR, 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) MnvtS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmfIO|IhcA>? Mo\ISG1UVw>? NWXJSGhuUUN3ME2xOVg3KMLzIEG3N{BvVQ>? NX3EZ4ZlOjV5NEmwN|Q>
WT 70 M4f5VGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUe3NkBp M2e1XmROW09? NX:5O3RDUUN3ME2yNUDDuSB6IH7N NEPtcFkzPTd2OUCzOC=>
G1128S 1022 MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1jHSFczKGh? Mn[zSG1UVw>? M13rc2lEPTB;MUCyJOKyKDN6IH7N NXvObHp2OjV5NEmwN|Q>
C1156F 1293 NIr4SIpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4\q[VczKGh? NFS0RVBFVVOR M3Tr[GlEPTB;MkG3JOKyKDFzNTDuUS=> NVvrVI1yOjV5NEmwN|Q>
I1171N 519 NVHCOWtOT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NH;sV4s4OiCq MVPEUXNQ MkL5TWM2OD1zOEegxtEhQDdibl2= Mm[wNlU4PDlyM{S=
I1171T 445 M4PTTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYW0ZVVpPzJiaB?= Ml72SG1UVw>? Mlm5TWM2OD16MjFCtUAyOiCwTR?= NV;4PGpyOjV5NEmwN|Q>
F1174I 184 MYXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV\LOZN2PzJiaB?= NGqxbplFVVOR M4XvRmlEPTB;MUOgxtEhOC5zIH7N NGflcmQzPTd2OUCzOC=>
N1178H 169 NG\tSHFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHGzWlA4OiCq MYDEUXNQ NFPlTIhKSzVyPUSyJOKyKDZibl2= NIDWfZczPTd2OUCzOC=>
E1210K 748 NUjvdYlnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MU[3NkBp MnT3SG1UVw>? NGPHbItKSzVyPUG4O{DDuSB6NDDuUS=> NFrvbWgzPTd2OUCzOC=>
C1156F/D1203N 2809 NHLZN3FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmrSO|IhcA>? Mn3vSG1UVw>? MVrJR|UxRTJ3NDFCtUA6QSCwTR?= MorqNlU4PDlyM{S=
Ba/F3 NA WT M4XTeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4DUPVczKGh? Ml36TWM2OD1yLkCyNEDPxE1? M2fxblI2PzJ5NECw
Ba/F3 NA C1156Y M{SyZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnLDO|IhcA>? MWDJR|UxRTBwMEexJO69VQ>? MmniNlU4Ojd2MEC=
Ba/F3 NA L1196M NYXpe2RpT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M335O|czKGh? M{DMVmlEPTB;MD6wOFIh|ryP MWGyOVczPzRyMB?=
Ba/F3 NA L1152R NH32NG5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXW3NkBp M2nweGlEPTB;MD6yPFgh|ryP Mme1NlU4Ojd2MEC=
Ba/F3 NA G1202R NWrBPJduT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{TQSFczKGh? M2rkXWlEPTB;MD6yO|ch|ryP Moi1NlU4Ojd2MEC=
Ba/F3 NA G1269A MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVu3NkBp MXnJR|UxRTBwMEG5JO69VQ>? NUHhT3dnOjV5Mke0NFA>
Ba/F3 NA S1206Y MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NYf0cpJIPzJiaB?= MU\JR|UxRTBwMEO3JO69VQ>? M2jkN|I2PzJ5NECw
Ba/F3 EA WT M3nvcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NX;wcW9XPzJiaB?= NHvw[HhKSzVyPUCuNFIyKM7:TR?= NWPRXpo5OjV5Mke0NFA>
Ba/F3 EA C1156Y NEnWb4tIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWLYT3JyPzJiaB?= M33VOWlEPTB;MD6wNlYh|ryP MlnKNlU4Ojd2MEC=
Ba/F3 EA L1196M M2DPUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH\pclk4OiCq MXnJR|UxRTBwMEG5JO69VQ>? MVuyOVczPzRyMB?=
Ba/F3 EA L1152R NHfZ[HZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYi3NkBp MV7JR|UxRTBwMEm5JO69VQ>? M3zTWlI2PzJ5NECw
Ba/F3 EA G1202R NEH6e5FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Mm\MO|IhcA>? MlK2TWM2OD1yLkS2O{DPxE1? NHG4bHkzPTd{N{SwNC=>
Ba/F3 EA G1269A MU\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1rMXFczKGh? MVTJR|UxRTBwMEOzJO69VQ>? NVjWTHhrOjV5Mke0NFA>
Ba/F3 EA S1206Y MnjTS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2f6U|czKGh? MXPJR|UxRTBwMEO4JO69VQ>? M{XyXlI2PzJ5NECw

... 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]
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  • 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
    (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

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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 Recruiting 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

Tech Support

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.

selleck catalog

ALK Signaling Pathway Map

ALK Inhibitors with Unique Features

  • Non-specific ALK Inhibitor

    GSK1838705A : IGF-1R, IC50=2.0 nM; IR, IC50=1.6 nM, ALK, IC50=0.5 nM.

  • FDA-approved ALK Inhibitor

    Crizotinib (PF-02341066) : Approved by FDA for non-small cell lung carcinoma (NSCLC).

  • Newest ALK Inhibitor

    ASP3026 New : Novel and selective inhibitor for ALK with IC50 of 3.5 nM.

  • Classic ALK Inhibitor

    TAE684 (NVP-TAE684) : Potent and selective ALK inhibitor with IC50 of 3 nM, 100-fold more sensitive for ALK than InsR.

Related ALK Products

  • Lorlatinib (PF-6463922) New

    PF-06463922 is a potent, dual ALK/ROS1 inhibitor with Ki of <0.02 nM, <0.07 nM, and 0.7 nM for ROS1, ALK (WT), and ALK (L1196M), respectively. Phase 1.

  • Erlotinib New

    Erlotinib is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.

  • R428 (BGB324|Bemcentinib) New

    R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).

  • TAE684 (NVP-TAE684)

    TAE684 (NVP-TAE684) is a potent and selective ALK inhibitor with IC50 of 3 nM in a cell-free assay, 100-fold more sensitive for ALK than InsR.

  • GSK1838705A

    GSK1838705A is a potent IGF-1R inhibitor with IC50 of 2.0 nM, modestly potent to IR and ALK with IC50 of 1.6 nM and 0.5 nM, respectively, and little activity to other protein kinases.

    Features:A small-molecule kinase inhibitor of IGF-1R and the insulin receptor.

  • Alectinib (CH5424802)

    Alectinib (CH5424802) is a potent ALK inhibitor with IC50 of 1.9 nM in cell-free assays, sensitive to L1196M mutation and higher selectivity for ALK than PF-02341066, NVP-TAE684 and PHA-E429.

  • AP26113-analog (ALK-IN-1)

    AP26113-analog (ALK-IN-1) is an analog of AP26113 which is a potent and selective ALK inhibitor. It is also an inhibitor of EGFR.

    Features:At least 10-fold more potent and selective in ALK inhibition relative to crizotinib.

  • ASP3026

    ASP3026 is a novel and selective inhibitor for ALK with IC50 of 3.5 nM. Phase 1.

  • AZD3463

    AZD3463 is a novel orally bioavailable ALK inhibitor with Ki of 0.75 nM, which also inhibits IGF1R with equivalent potency.

  • Gefitinib (ZD1839)

    Gefitinib (ZD-1839) is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively.

    Features:A potent EGFR tyrosine kinase inhibitor.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID