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.

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.

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)	MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MYK3NkBp	NHW5WnlFVVOR	NYHTdWhDUUN3ME2xOVg3KMLzIEG3N{BvVQ>?	MYKyOVc1QTB\|NB?=
WT 70	M1O1RWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	MnfuO\|IhcA>?	MkLPSG1UVw>?	MnvJTWM2OD1{MTFCtUA5KG6P	M4TYclI2PzR7MEO0
G1128S 1022	MVnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NFzacnk4OiCq	NGLJeodFVVOR	NF7CPXZKSzVyPUGwNkDDuSB\|ODDuUS=>	MmDhNlU4PDlyM{S=
C1156F 1293	M{P6VWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NGXPfms4OiCq	NIjUeYVFVVOR	M3uzTWlEPTB;MkG3JOKyKDFzNTDuUS=>	NEjqUm0zPTd2OUCzOC=>
I1171N 519	NIfnZXBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NX:yOolLPzJiaB?=	MUnEUXNQ	M{m1cmlEPTB;MUi3JOKyKDh5IH7N	MYeyOVc1QTB\|NB?=
I1171T 445	NF3qe41Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NX;YSGZqPzJiaB?=	MY\EUXNQ	NED5eFJKSzVyPUiyJOKyKDF{IH7N	NVTwTYFQOjV5NEmwN\|Q>
F1174I 184	MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NIH5OFQ4OiCq	M3LtO2ROW09?	NH;oOHlKSzVyPUGzJOKyKDBwMTDuUS=>	NXjmWnFZOjV5NEmwN\|Q>
N1178H 169	M2TwR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NUT2Z4FLPzJiaB?=	MVPEUXNQ	NW\YOmFmUUN3ME20NkDDuSB4IH7N	NYSx[VlVOjV5NEmwN\|Q>
E1210K 748	MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NGLMNGo4OiCq	NX;UN3B1TE2VTx?=	M2Gx[GlEPTB;MUi3JOKyKDh2IH7N	M4O5VVI2PzR7MEO0
C1156F/D1203N 2809	MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MlHQO\|IhcA>?	M4HsdGROW09?	NXLuZW01UUN3ME2yOVQhyrFiOUmgcm0>	NE\YXnMzPTd2OUCzOC=>
Ba/F3 NA WT	NVvDWYZjT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	NUizSXB[PzJiaB?=		MkG2TWM2OD1yLkCyNEDPxE1?	NIT3eIMzPTd{N{SwNC=>
Ba/F3 NA C1156Y	MkLJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MX63NkBp		M3i4WWlEPTB;MD6wO\|Eh\|ryP	NGiyblUzPTd{N{SwNC=>
Ba/F3 NA L1196M	M1y1XWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	MVu3NkBp		NWjWTGVIUUN3ME2wMlA1OiEQvF2=	NH3HUo0zPTd{N{SwNC=>
Ba/F3 NA L1152R	NVHPN3kyT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	Mk\WO\|IhcA>?		MVHJR\|UxRTBwMki4JO69VQ>?	MlHxNlU4Ojd2MEC=
Ba/F3 NA G1202R	NUXjfoNGT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MkfYO\|IhcA>?		MYTJR\|UxRTBwMke3JO69VQ>?	MlL0NlU4Ojd2MEC=
Ba/F3 NA G1269A	MmGwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M1LHb\|czKGh?		NGHuPHNKSzVyPUCuNFE6KM7:TR?=	MXSyOVczPzRyMB?=
Ba/F3 NA S1206Y	NYfteXp4T3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	NXn6ZoFYPzJiaB?=		MmW2TWM2OD1yLkCzO{DPxE1?	NWjifZkyOjV5Mke0NFA>
Ba/F3 EA WT	MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MYK3NkBp		MlvpTWM2OD1yLkCyNUDPxE1?	NEfOfVYzPTd{N{SwNC=>
Ba/F3 EA C1156Y	NWLJdXMxT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	NYPscoFnPzJiaB?=		M361UGlEPTB;MD6wNlYh\|ryP	MnnENlU4Ojd2MEC=
Ba/F3 EA L1196M	Mk\FS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	MWe3NkBp		M{\F[mlEPTB;MD6wNVkh\|ryP	MXmyOVczPzRyMB?=
Ba/F3 EA L1152R	M1rRe2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NIjaSGg4OiCq		NIjTOVBKSzVyPUCuNFk6KM7:TR?=	M4LFWlI2PzJ5NECw
Ba/F3 EA G1202R	M1nrVWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NFzwbIs4OiCq		M123W2lEPTB;MD60Olch\|ryP	MV:yOVczPzRyMB?=
Ba/F3 EA G1269A	NGnqenRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MnXUO\|IhcA>?		NIrNUnBKSzVyPUCuNFM{KM7:TR?=	NYPsTIxXOjV5Mke0NFA>
Ba/F3 EA S1206Y	NVzw[ZNPT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	MUC3NkBp		NGPhXW5KSzVyPUCuNFM5KM7:TR?=	NEjPe4szPTd{N{SwNC=>

... 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 2018-11-16)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT03399487	Not yet recruiting	Non-small Cell Lung Cancer Harboring ROS1 Rearrangement	Yonsei University	January 2018	Phase 2
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	May 6 2016	Phase 2
NCT02450903	Completed	Non-Small-Cell Lung Cancer	Novartis Pharmaceuticals\|Novartis	August 21 2015	Phase 2
NCT02393625	Recruiting	ALK-positive NSCLC	Novartis Pharmaceuticals\|Novartis	May 27 2015	Phase 1
NCT02336451	Recruiting	ALK-positive Non-small Cell Lung Cancer	Novartis Pharmaceuticals\|Novartis	April 1 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

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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.

Related ALK Products4

Lorlatinib (PF-6463922) ^New

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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) ^New

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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.
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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

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Features:A potent EGFR tyrosine kinase inhibitor.

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Ceritinib (LDK378)