Ceritinib (LDK378)

Catalog No.S7083

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.

3 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.
(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.

Purity & Quality Control

Choose Selective ALK Inhibitors

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	Incubation Time	Formulation	Activity Description	PMID
Parental(+IL3)	MoDQS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NVjjRXNZPzJiaB?=	M3:0ZWROW09?	NGfwSJdKSzVyPUG1PFYhyrFiMUezJI5O	M2CwflI2PzR7MEO0
WT 70	MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NWrXcYIxPzJiaB?=	M1ywcGROW09?	MX3JR\|UxRTJzINMxJFghdk1?	NFfIS4czPTd2OUCzOC=>
G1128S 1022	Mo\qS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M1qwclczKGh?	NGLnT3FFVVOR	NIDNO4dKSzVyPUGwNkDDuSB\|ODDuUS=>	MXeyOVc1QTB\|NB?=
C1156F 1293	NEjBSVNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MkjkO\|IhcA>?	MmOzSG1UVw>?	MUfJR\|UxRTJzNzFCtUAyOTVibl2=	MVOyOVc1QTB\|NB?=
I1171N 519	NXPuS2MxT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	NFfTWHc4OiCq	MmXKSG1UVw>?	MVfJR\|UxRTF6NzFCtUA5PyCwTR?=	M1jXVFI2PzR7MEO0
I1171T 445	MVzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MVi3NkBp	NW\ZeJhxTE2VTx?=	MlX2TWM2OD16MjFCtUAyOiCwTR?=	NIL5[GEzPTd2OUCzOC=>
F1174I 184	M37Rd2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NFroT204OiCq	NFfiTXVFVVOR	MYTJR\|UxRTF\|INMxJFAvOSCwTR?=	MojINlU4PDlyM{S=
N1178H 169	MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MYe3NkBp	M2LMfGROW09?	NHq1[GlKSzVyPUSyJOKyKDZibl2=	Mnz6NlU4PDlyM{S=
E1210K 748	MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MnPJO\|IhcA>?	MonxSG1UVw>?	NIXCPYpKSzVyPUG4O{DDuSB6NDDuUS=>	MmjlNlU4PDlyM{S=
C1156F/D1203N 2809	MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	M3XiblczKGh?	MUHEUXNQ	MkLGTWM2OD1{NUSgxtEhQTlibl2=	M2fz[FI2PzR7MEO0
Ba/F3 NA WT	M3HLT2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NH\GZ4E4OiCq		Ml64TWM2OD1yLkCyNEDPxE1?	MXuyOVczPzRyMB?=
Ba/F3 NA C1156Y	MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MV:3NkBp		NGXjcWFKSzVyPUCuNFcyKM7:TR?=	NIroOHczPTd{N{SwNC=>
Ba/F3 NA L1196M	M3ToR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	MVm3NkBp		MVvJR\|UxRTBwMESyJO69VQ>?	NGPqVXEzPTd{N{SwNC=>
Ba/F3 NA L1152R	MmfHS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NVjRWZNsPzJiaB?=		MX;JR\|UxRTBwMki4JO69VQ>?	NHT1VIozPTd{N{SwNC=>
Ba/F3 NA G1202R	MkTUS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NE\yNpA4OiCq		NXK2Ro4xUUN3ME2wMlI4PyEQvF2=	MXuyOVczPzRyMB?=
Ba/F3 NA G1269A	M4n4Wmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NYXYe\|JEPzJiaB?=		M3;CZmlEPTB;MD6wNVkh\|ryP	M4LBfVI2PzJ5NECw
Ba/F3 NA S1206Y	Mo[0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MYS3NkBp		NXHqe29CUUN3ME2wMlA{PyEQvF2=	NIruVoczPTd{N{SwNC=>
Ba/F3 EA WT	NWK1OGtzT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MmW0O\|IhcA>?		NWfacJJ5UUN3ME2wMlAzOSEQvF2=	MUGyOVczPzRyMB?=
Ba/F3 EA C1156Y	NHTmNYVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NHf1cno4OiCq		MV;JR\|UxRTBwMEK2JO69VQ>?	NVOyZo9iOjV5Mke0NFA>
Ba/F3 EA L1196M	NHvKWHhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NGi4c2o4OiCq		M4LJfWlEPTB;MD6wNVkh\|ryP	MYiyOVczPzRyMB?=
Ba/F3 EA L1152R	MlXnS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NFy5Oog4OiCq		M{HobGlEPTB;MD6wPVkh\|ryP	M2r4clI2PzJ5NECw
Ba/F3 EA G1202R	NWKxcY1RT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	NITZ[pQ4OiCq		M330cWlEPTB;MD60Olch\|ryP	MXeyOVczPzRyMB?=
Ba/F3 EA G1269A	NEflSY5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	Mni0O\|IhcA>?		NVe0V3d{UUN3ME2wMlA{OyEQvF2=	MYmyOVczPzRyMB?=
Ba/F3 EA S1206Y	NYH2VY5RT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MVW3NkBp		MV;JR\|UxRTBwMEO4JO69VQ>?	M2HJNlI2PzJ5NECw

... 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]

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)

References

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

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 Download Ceritinib (LDK378) SDF

Molecular Weight	558.14
Formula	C₂₈H₃₆ClN₅O₃S
CAS No.	1032900-25-6
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	N/A

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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2018-10-19)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01828099	Active not recruiting	Non-Small Cell Lung Cancer	Novartis Pharmaceuticals\|Novartis	July 9 2013	Phase 3
NCT02040870	Completed	Non-Small Cell Lung Cancer	Novartis Pharmaceuticals\|Novartis	March 7 2014	Phase 1\|Phase 2
NCT01742286	Recruiting	Anaplastic Lymphoma Kinase	Novartis Pharmaceuticals\|Novartis	August 28 2013	Phase 1
NCT01828112	Active not recruiting	Non-Small Cell Lung Cancer	Novartis Pharmaceuticals\|Novartis	June 28 2013	Phase 3
NCT01685060	Completed	Non-Small Cell Lung Cancer	Novartis Pharmaceuticals\|Novartis	November 26 2012	Phase 2
NCT02450903	Completed	Non-Small-Cell Lung Cancer	Novartis Pharmaceuticals\|Novartis	August 21 2015	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.

Handling Instructions

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

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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.

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.

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Ceritinib (LDK378)