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 10 Publications

5 Customer Reviews

  • Quantitation of crystal violet uptake by ORF-expressing cells exposed to crizotinib (CRZ) or ceritinib (CER) normalized to Lac Z. Mean and SE are shown for six (CRZ) or four (CER) independent experiments of three replicates each.

    Cancer Cell, 2015, 27(3): 397-408 . Ceritinib (LDK378) purchased from Selleck.

    H3122 cells expressing pRS or shSMARCE1 vectors were cultured in the absence or presence of 100 nM NVP-TAE684, 400 nM Ceritinib, 1 μM gefitinib or their combination for 3 h. Cell lysates were harvested for immunoblot analysis and probed for the indicated proteins.

    Cell Res, 2015, 25(4): 445-58. Ceritinib (LDK378) purchased from Selleck.

  • Immunoblot of BEAS-2B/LacZ and BEAS-2B/EA samples treated with serially diluted concentration of crizotinib (CZT) and ceritinib (CER; 0, 0.01, 0.1, 0.5, and 1 μmol/L) for 48 hours. Results are shown as means ± SD (N=3).

    Clin Cancer Res, 2018, doi:10.1158/1078-0432. Ceritinib (LDK378) purchased from Selleck.

    Immunoblots of integrin b3 expression in H3122 and H2228 cells treated with DMSO (0 mmol/L), 1 mmol/L crizotinib (CZT), or 1 mmol/L ceritinib (CER) for 48 hours.

    Clin Cancer Res, 2018, 24(17):4162-4174. Ceritinib (LDK378) purchased from Selleck.

  • (A) H3122 LDK_R show increased invasive and migratory capabilities compared to parental H3122, (B) loss of E-cadherin and increased mesenchymal markers including vimentin and AXL. Knockdown of vimentin decreased AXL expression in H3122 LDK_R.

    Mol Oncol, 2016, 10(4):601-9. Ceritinib (LDK378) purchased from Selleck.

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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) MlrwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MU[3NkBp MnzySG1UVw>? NHP6OXpKSzVyPUG1PFYhyrFiMUezJI5O M2jPeFI2PzR7MEO0
WT 70 MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4XmRVczKGh? M17ab2ROW09? M4L4NmlEPTB;MkGgxtEhQCCwTR?= NHPWV5EzPTd2OUCzOC=>
G1128S 1022 M1fjNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVi3NkBp MYfEUXNQ Ml\mTWM2OD1zMEKgxtEhOzhibl2= NHPj[ZczPTd2OUCzOC=>
C1156F 1293 MX3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkfJO|IhcA>? MXnEUXNQ NYC4Zo1EUUN3ME2yNVchyrFiMUG1JI5O MWCyOVc1QTB|NB?=
I1171N 519 NWDidY9WT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXK3NkBp NED0fG9FVVOR NXXvUlFvUUN3ME2xPFchyrFiOEegcm0> MoPkNlU4PDlyM{S=
I1171T 445 MmHIS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MUC3NkBp NVzi[pZXTE2VTx?= MVLJR|UxRTh{INMxJFEzKG6P MlLUNlU4PDlyM{S=
F1174I 184 NGC0V4JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MU[3NkBp NHjtfodFVVOR Mk[2TWM2OD1zMzFCtUAxNjFibl2= NVry[2ZTOjV5NEmwN|Q>
N1178H 169 M{m5Xmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVjWVFhjPzJiaB?= NYPB[HAxTE2VTx?= NGTjcJVKSzVyPUSyJOKyKDZibl2= MnjONlU4PDlyM{S=
E1210K 748 M1ribWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MliwO|IhcA>? NHHRS3VFVVOR NWDXUYZvUUN3ME2xPFchyrFiOESgcm0> NF;lbZQzPTd2OUCzOC=>
C1156F/D1203N 2809 MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4jERlczKGh? NVPZZYZ7TE2VTx?= MVHJR|UxRTJ3NDFCtUA6QSCwTR?= NInZ[XYzPTd2OUCzOC=>
Ba/F3 NA WT MmLxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoTyO|IhcA>? MW\JR|UxRTBwMEKwJO69VQ>? NWXjcIs3OjV5Mke0NFA>
Ba/F3 NA C1156Y MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlHIO|IhcA>? M2fJSWlEPTB;MD6wO|Eh|ryP NVTXUpFKOjV5Mke0NFA>
Ba/F3 NA L1196M MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MojGO|IhcA>? NH\rOHdKSzVyPUCuNFQzKM7:TR?= MY[yOVczPzRyMB?=
Ba/F3 NA L1152R NYLS[4tHT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHTXTFc4OiCq NHnGbo5KSzVyPUCuNlg5KM7:TR?= MkPPNlU4Ojd2MEC=
Ba/F3 NA G1202R NW\MPFRzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkT6O|IhcA>? MmL6TWM2OD1yLkK3O{DPxE1? NX\Z[3QxOjV5Mke0NFA>
Ba/F3 NA G1269A M4DLSGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3jlWlczKGh? NFfvOFNKSzVyPUCuNFE6KM7:TR?= MVuyOVczPzRyMB?=
Ba/F3 NA S1206Y NVXqfFN7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M17mVlczKGh? NFjKNIpKSzVyPUCuNFM4KM7:TR?= NFO4TIYzPTd{N{SwNC=>
Ba/F3 EA WT NEHNO3FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFLDRlY4OiCq NYfXVoJjUUN3ME2wMlAzOSEQvF2= MlTTNlU4Ojd2MEC=
Ba/F3 EA C1156Y MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1q1S|czKGh? MVnJR|UxRTBwMEK2JO69VQ>? Mke2NlU4Ojd2MEC=
Ba/F3 EA L1196M Mmn1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIHtV4c4OiCq MmmxTWM2OD1yLkCxPUDPxE1? NFnjXFkzPTd{N{SwNC=>
Ba/F3 EA L1152R NVfaRYlkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4H4cVczKGh? NVntNZA{UUN3ME2wMlA6QSEQvF2= NYTreJk1OjV5Mke0NFA>
Ba/F3 EA G1202R MWLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnnFO|IhcA>? NH\LcWJKSzVyPUCuOFY4KM7:TR?= NWW1WXNkOjV5Mke0NFA>
Ba/F3 EA G1269A NXe3SFRDT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXK3NkBp NFHHXZpKSzVyPUCuNFM{KM7:TR?= M{XnXVI2PzJ5NECw
Ba/F3 EA S1206Y NEfJc2JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{XhVlczKGh? MUjJR|UxRTBwMEO4JO69VQ>? MXSyOVczPzRyMB?=

... 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]
+ Expand

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]
+ Expand
  • 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]
+ Expand
  • 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 Conditions Sponsor/Collaborators Start Date Phases
NCT03399487 Recruiting Non-small Cell Lung Cancer Harboring ROS1 Rearrangement Yonsei University July 24 2018 Phase 2
NCT03399487 Recruiting Non-small Cell Lung Cancer Harboring ROS1 Rearrangement Yonsei University July 24 2018 Phase 2
NCT02321501 Recruiting Head and Neck Cancer|Lung Cancer M.D. Anderson Cancer Center|Novartis June 2016 Phase 1
NCT02321501 Recruiting Head and Neck Cancer|Lung Cancer M.D. Anderson Cancer Center|Novartis June 2016 Phase 1
NCT02465528 Completed Tumors With Aberrations in ALK Novartis Pharmaceuticals|Novartis May 6 2016 Phase 2
NCT02465528 Completed Tumors With Aberrations in ALK Novartis Pharmaceuticals|Novartis May 6 2016 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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID