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)	NGj6N5NIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NFjlO4w4OiCq	NYKyVnBXTE2VTx?=	NYHEUGFqUUN3ME2xOVg3KMLzIEG3N{BvVQ>?	NG\ublgzPTd2OUCzOC=>
WT 70	NHj1cWRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MUG3NkBp	MVfEUXNQ	MX;JR\|UxRTJzINMxJFghdk1?	M{X6bFI2PzR7MEO0
G1128S 1022	MlzRS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NVzYWnJCPzJiaB?=	NVi4enBnTE2VTx?=	M1PjNWlEPTB;MUCyJOKyKDN6IH7N	MkHFNlU4PDlyM{S=
C1156F 1293	NIKxNolIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	M2XpPFczKGh?	MnW5SG1UVw>?	NEnIW2ZKSzVyPUKxO{DDuSBzMUWgcm0>	M1f0PFI2PzR7MEO0
I1171N 519	Mmj0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	M2nzOlczKGh?	MlLsSG1UVw>?	NV\ZWWdnUUN3ME2xPFchyrFiOEegcm0>	NIq2V2czPTd2OUCzOC=>
I1171T 445	M3Xuc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	MXq3NkBp	NX7ZVVE1TE2VTx?=	MoHtTWM2OD16MjFCtUAyOiCwTR?=	MYmyOVc1QTB\|NB?=
F1174I 184	M3joNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	M{KwU\|czKGh?	MU\EUXNQ	MoqyTWM2OD1zMzFCtUAxNjFibl2=	MoHNNlU4PDlyM{S=
N1178H 169	MWfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	M4Tu[lczKGh?	M{XWU2ROW09?	NHjKSWdKSzVyPUSyJOKyKDZibl2=	NW\HWHNJOjV5NEmwN\|Q>
E1210K 748	NELzV4pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NVH3VWxrPzJiaB?=	M3\0OmROW09?	M3Syc2lEPTB;MUi3JOKyKDh2IH7N	M3T4VFI2PzR7MEO0
C1156F/D1203N 2809	MlzBS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?	NX;vWYd4PzJiaB?=	NXr3PVRFTE2VTx?=	NIq1OYpKSzVyPUK1OEDDuSB7OTDuUS=>	M2iycFI2PzR7MEO0
Ba/F3 NA WT	MXPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	M2raSlczKGh?		NI\HflZKSzVyPUCuNFIxKM7:TR?=	MoT5NlU4Ojd2MEC=
Ba/F3 NA C1156Y	NHG2Z4VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	MUG3NkBp		M2W1PWlEPTB;MD6wO\|Eh\|ryP	MnHLNlU4Ojd2MEC=
Ba/F3 NA L1196M	NFj2ZpBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NXTlSpJCPzJiaB?=		NYrIe\|NoUUN3ME2wMlA1OiEQvF2=	M2DJSlI2PzJ5NECw
Ba/F3 NA L1152R	M4HRV2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NYXQ[ZMyPzJiaB?=		NH\CbVNKSzVyPUCuNlg5KM7:TR?=	NGLEZnozPTd{N{SwNC=>
Ba/F3 NA G1202R	M4nEVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NGTlXok4OiCq		MXrJR\|UxRTBwMke3JO69VQ>?	NVPpdJZvOjV5Mke0NFA>
Ba/F3 NA G1269A	MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MoS3O\|IhcA>?		MUPJR\|UxRTBwMEG5JO69VQ>?	M1nL[FI2PzJ5NECw
Ba/F3 NA S1206Y	NEG4TmhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NH3Fb3M4OiCq		M4nWTGlEPTB;MD6wN\|ch\|ryP	M1jLbFI2PzJ5NECw
Ba/F3 EA WT	MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	MmXTO\|IhcA>?		MWDJR\|UxRTBwMEKxJO69VQ>?	NVG1bXJ4OjV5Mke0NFA>
Ba/F3 EA C1156Y	NV3uV3pWT3Kxd4ToJGlvcGmkaYTpc44hSXO\|YYm=	M3;1PFczKGh?		M1\TPWlEPTB;MD6wNlYh\|ryP	NFzLVZQzPTd{N{SwNC=>
Ba/F3 EA L1196M	M{X1O2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7	NGL0V4c4OiCq		Ml\DTWM2OD1yLkCxPUDPxE1?	NUfuPHpkOjV5Mke0NFA>
Ba/F3 EA L1152R	MV\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?	NF;OUGc4OiCq		NHjYcopKSzVyPUCuNFk6KM7:TR?=	MW[yOVczPzRyMB?=
Ba/F3 EA G1202R	NFH0[XdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NECwWVY4OiCq		M1roW2lEPTB;MD60Olch\|ryP	M4r3VVI2PzJ5NECw
Ba/F3 EA G1269A	NIr0TWtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	NUO5R49oPzJiaB?=		NIXTWXBKSzVyPUCuNFM{KM7:TR?=	Ml7rNlU4Ojd2MEC=
Ba/F3 EA S1206Y	NFn1bJpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=	M1mxblczKGh?		MoHiTWM2OD1yLkCzPEDPxE1?	NFTpdVIzPTd{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

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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.

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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Lorlatinib (PF-6463922) ^New

PF-06463922 is a potent, dual ALK/ROS1 inhibitor with K_i 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) ^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.
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.
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Features:A potent EGFR tyrosine kinase inhibitor.

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Ceritinib (LDK378)