Ceritinib (LDK378)

Catalog No.S7083

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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Ceritinib (LDK378) Chemical Structure

Ceritinib (LDK378) Chemical Structure
Molecular Weight: 558.14

Validation & Quality Control

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Quality Control & MSDS

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 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.

Product Information

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  • Research Area
  • Inhibition Profile

Product Description

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.
Targets ALK [1]
(Cell-free assay)
Insulin Receptor [1]
(Cell-free assay)
IGF-1R [1]
(Cell-free assay)
STK22D [1]
(Cell-free assay)

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IC50 0.2 nM 7 nM 8 nM 23 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 LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
Parental(+IL3)MkDDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M3LJWVczKGh?NYWwRnU3TE2VTx?=NHTIVGFKSzVyPUG1PFYhyrFiMUezJI5ONEHESHIzPTd2OUCzOC=>
WT 70NHX0NYFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NEXsN5Y4OiCqNXnDe3pSTE2VTx?=NWDoU5JTUUN3ME2yNUDDuSB6IH7NNYDONXZ2OjV5NEmwN|Q>
G1128S 1022NXfDSph{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M3ToRVczKGh?NXf0e5RNTE2VTx?=MY\JR|UxRTFyMjFCtUA{QCCwTR?=MUmyOVc1QTB|NB?=
C1156F 1293NXvqN4pkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M3nxe|czKGh?NVPzfpJ[TE2VTx?=MkfDTWM2OD1{MUegxtEhOTF3IH7NMX[yOVc1QTB|NB?=
I1171N 519NYrkUYc3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M3vkS|czKGh?NIK4dmtFVVORNX;IPYYzUUN3ME2xPFchyrFiOEegcm0>NF\US2UzPTd2OUCzOC=>
I1171T 445M4jTVWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7M2DaTFczKGh?MYfEUXNQNGq0foZKSzVyPUiyJOKyKDF{IH7NNGr1OpMzPTd2OUCzOC=>
F1174I 184M2WyRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NX3KbJJvPzJiaB?=NWPabll[TE2VTx?=M2TDSWlEPTB;MUOgxtEhOC5zIH7NNE\zXGQzPTd2OUCzOC=>
N1178H 169NV[2dI9tT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MkDTO|IhcA>?M3zFSGROW09?M362OGlEPTB;NEKgxtEhPiCwTR?=MYOyOVc1QTB|NB?=
E1210K 748NHzn[GhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NV;s[XJKPzJiaB?=NEDZfGlFVVORNFLLfFlKSzVyPUG4O{DDuSB6NDDuUS=>NVG2[2ZWOjV5NEmwN|Q>
C1156F/D1203N 2809Ml\yS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M{n0[|czKGh?NUOxR3BpTE2VTx?=NUDZemhsUUN3ME2yOVQhyrFiOUmgcm0>NVr1fJNJOjV5NEmwN|Q>
Ba/F3 NA WTMl:wS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MnS0O|IhcA>?NYfZOnl1UUN3ME2wMlAzOCEQvF2=MWSyOVczPzRyMB?=
Ba/F3 NA C1156YM1vh[Wdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NVjZVIY3PzJiaB?=MXLJR|UxRTBwMEexJO69VQ>?NFr1[ZkzPTd{N{SwNC=>
Ba/F3 NA L1196MNUOzTGtiT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MmnVO|IhcA>?NYHRNHNFUUN3ME2wMlA1OiEQvF2=NH:2WogzPTd{N{SwNC=>
Ba/F3 NA L1152RM4DM[Wdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MkjSO|IhcA>?NIjtfotKSzVyPUCuNlg5KM7:TR?=MXmyOVczPzRyMB?=
Ba/F3 NA G1202RNFLKPI9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=Ml3tO|IhcA>?NHT6PIVKSzVyPUCuNlc4KM7:TR?=MV6yOVczPzRyMB?=
Ba/F3 NA G1269ANEf5fXZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=M1rhS|czKGh?NFHCfXFKSzVyPUCuNFE6KM7:TR?=M3K3c|I2PzJ5NECw
Ba/F3 NA S1206YMorMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MW[3NkBpMY\JR|UxRTBwMEO3JO69VQ>?NIDRSXgzPTd{N{SwNC=>
Ba/F3 EA WTNVLQPHROT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NF:2epI4OiCqMlHsTWM2OD1yLkCyNUDPxE1?NV7ySVVXOjV5Mke0NFA>
Ba/F3 EA C1156YNGjFe4lIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MoTYO|IhcA>?MlPNTWM2OD1yLkCyOkDPxE1?MX2yOVczPzRyMB?=
Ba/F3 EA L1196MM3LKUGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NIm2b5Q4OiCqM4TXeGlEPTB;MD6wNVkh|ryPNUHpOIxSOjV5Mke0NFA>
Ba/F3 EA L1152RMUDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MkPyO|IhcA>?NV21NZJ5UUN3ME2wMlA6QSEQvF2=Mn7YNlU4Ojd2MEC=
Ba/F3 EA G1202RNWX1WFZjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M3TKclczKGh?M2PjPWlEPTB;MD60Olch|ryPMnruNlU4Ojd2MEC=
Ba/F3 EA G1269AM3PJN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7NUjxcFAyPzJiaB?=NEHXZmZKSzVyPUCuNFM{KM7:TR?=MnXlNlU4Ojd2MEC=
Ba/F3 EA S1206YNV7k[3pTT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=M1PV[FczKGh?MXnJR|UxRTBwMEO4JO69VQ>?M3\SXFI2PzJ5NECw

... Click to View More Cell Line Experimental Data

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]
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.

Protocol(Only for Reference)

Kinase Assay: [1]

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 Assay: [1]

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.

Animal Study: [1]

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

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Marsilje TH, et al. J Med Chem. 2013, Jun 6.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02321501 Recruiting Head and Neck Cancer|Lung Cancer M.D. Anderson Cancer Center|Novartis June 2016 Phase 1
NCT02465528 Recruiting Tumors With Aberrations in ALK Novartis Pharmaceuticals|Novartis March 2016 Phase 2
NCT02450903 Recruiting Non-Small-Cell Lung Cancer Novartis Pharmaceuticals|Novartis August 2015 Phase 2
NCT02393625 Recruiting ALK-positive NSCLC Novartis Pharmaceuticals|Novartis May 2015 Phase 1
NCT02336451 Recruiting ALK-positive NSCLC Metastatic to the Brain and/or to Leptomeninges. Novartis Pharmaceuticals|Novartis April 2015 Phase 2

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Chemical Information

Download Ceritinib (LDK378) SDF
Molecular Weight (MW) 558.14
Formula

C28H36ClN5O3S

CAS No. 1032900-25-6
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 20 mg/mL warming (35.83 mM)
Ethanol 3 mg/mL (5.37 mM)
Water <1 mg/mL
* <1 mg/ml means slightly soluble or 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 Name 2,4-Pyrimidinediamine, 5-chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-

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.

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.

Tel: +1-832-582-8158 Ext:3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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