Identification

Name
Ceritinib
Accession Number
DB09063
Type
Small Molecule
Groups
Approved
Description

Ceritinib is used for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) following failure (secondary to resistance or intolerance) of prior crizotinib therapy. About 4% of patients with NSCLC have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Following treatment with crizotinib (a first-generation ALK inhibitor), most tumours develop drug resistance due to mutations in key "gatekeeper" residues of the enzyme. This occurrence led to development of novel second-generation ALK inhibitors such as ceritinib to overcome crizotinib resistance. The FDA approved ceritinib in April 2014 due to a surprisingly high response rate (56%) towards crizotinib-resistant tumours and has designated it with orphan drug status.

Structure
Thumb
Synonyms
  • céritinib
  • N-{2-[(5-chloro-2-{[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)amino]phenyl}propane-2-sulfonamide
External IDs
LDK 378 / LDK-378 / LDK378 / NVP-LDK378-NX
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZykadiaCapsule150 mgOralNovartis2015-04-29Not applicableCanada
ZykadiaCapsule150 mgOralNovartis Europharm Limited2015-05-06Not applicableEu
ZykadiaCapsule150 mgOralNovartis Europharm Limited2015-05-06Not applicableEu
ZykadiaCapsule150 mg/1OralNovartis Pharmaceuticals Corporation2014-04-29Not applicableUs
Categories
UNII
K418KG2GET
CAS number
1032900-25-6
Weight
Average: 558.135
Monoisotopic: 557.22273844
Chemical Formula
C28H36ClN5O3S
InChI Key
VERWOWGGCGHDQE-UHFFFAOYSA-N
InChI
InChI=1S/C28H36ClN5O3S/c1-17(2)37-25-15-21(20-10-12-30-13-11-20)19(5)14-24(25)33-28-31-16-22(29)27(34-28)32-23-8-6-7-9-26(23)38(35,36)18(3)4/h6-9,14-18,20,30H,10-13H2,1-5H3,(H2,31,32,33,34)
IUPAC Name
5-chloro-N2-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine
SMILES
CC(C)OC1=C(NC2=NC=C(Cl)C(N2)=NC2=CC=CC=C2S(=O)(=O)C(C)C)C=C(C)C(=C1)C1CCNCC1

Pharmacology

Indication

Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats.

TargetActionsOrganism
AALK tyrosine kinase receptor
antagonist
Human
Absorption

After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours.

Volume of distribution

The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose.

Protein binding

Ceritinib is 97% bound to human plasma proteins, independent of drug concentration.

Metabolism

In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma.

Route of elimination

Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.

Half life

The terminal half life is 41 hours.

Clearance

The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h).

Toxicity

There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Ceritinib.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Ceritinib.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Ceritinib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Ceritinib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Ceritinib.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Ceritinib.
6-Deoxyerythronolide BThe metabolism of Ceritinib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Ceritinib.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Ceritinib.
AbemaciclibThe serum concentration of Ceritinib can be increased when it is combined with Abemaciclib.
Food Interactions
Not Available

References

Synthesis Reference

Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26. Pubmed

General References
  1. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. doi: 10.1056/NEJMoa1311107. [PubMed:24670165]
  2. Nishio M, Murakami H, Horiike A, Takahashi T, Hirai F, Suenaga N, Tajima T, Tokushige K, Ishii M, Boral A, Robson M, Seto T: Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors. J Thorac Oncol. 2015 Jul;10(7):1058-66. doi: 10.1097/JTO.0000000000000566. [PubMed:26020125]
  3. Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, Wan Y, Ding P, Liu Y, Sun F, Schultz PG, Gray NS, Warmuth M: Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. Epub 2006 Dec 21. [PubMed:17185414]
  4. Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26. [PubMed:23742252]
  5. Mano H: The EML4-ALK oncogene: targeting an essential growth driver in human cancer. Proc Jpn Acad Ser B Phys Biol Sci. 2015;91(5):193-201. doi: 10.2183/pjab.91.193. [PubMed:25971657]
External Links
KEGG Drug
D10551
PubChem Compound
57379345
PubChem Substance
310264998
ChemSpider
29315053
BindingDB
50436850
ChEBI
78432
ChEMBL
CHEMBL2403108
HET
4MK
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ceritinib
ATC Codes
L01XE28 — Ceritinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
4mkc
FDA label
Download (307 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingNot AvailableGlioblastomas / Metastatic Brain Tumors1
1CompletedBasic ScienceTumors Characterized by Genetic Alterations in Anaplastic Lymphoma Kinase (ALK)1
1CompletedOtherALK-positive Advanced Tumors1
1CompletedTreatmentAnaplastic Lymphoma Kinase (ALK) / Lung Cancer Non-Small Cell Cancer (NSCLC)1
1CompletedTreatmentImpaired Hepatic Function / Normal Hepatic Function1
1CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1CompletedTreatmentTumors Characterized by Genetic Abnormalities of ALK1
1RecruitingTreatmentAdenocarcinoma of the Pancreas / Adult Solid Neoplasm / Advanced Malignant Solid Neoplasm / ALK positive / Pancreatic Adenocarcinoma Metastatic / Solid Neoplasms / Stage III Pancreatic Cancer / Stage IV Pancreatic Cancer1
1RecruitingTreatmentALK-positive NSCLC1
1RecruitingTreatmentAnaplastic Lymphoma Kinase / Anaplastic Lymphoma Kinase (ALK)1
1RecruitingTreatmentEGFR Negative Non-Small Cell Lung Cancer / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancers / Metastatic Non-Small Cell Lung Cancer / Non-Small Cell Lung Cancer Stage IIIB / Stage IV Non-Small Cell Lung Cancer1
1RecruitingTreatmentHead and Neck Carcinoma / Lung Cancers1
1RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1RecruitingTreatmentMalignancies / Neuroblastomas1
1, 2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1, 2RecruitingTreatmentAnaplastic Large Cell Lymphoma, ALK-Positive / CD30-Positive Neoplastic Cells Present / Systemic Anaplastic Large Cell Lymphoma1
1, 2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2Active Not RecruitingTreatmentAdenocarcinoma Lung Cancer / Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)3
2CompletedTreatmentTumors With Aberrations in ALK1
2CompletedTreatmentTumors With Aberrations in ALK or ROS11
2Not Yet RecruitingScreeningALK Gene Rearrangement / ALK positive / Non-Squamous Non-Small Cell Lung Carcinoma / Stage IV Lung Cancer AJCC v8 / Stage IVA Lung Cancer AJCC v8 / Stage IVB Lung Cancer AJCC v81
2Not Yet RecruitingTreatmentNon-small Cell Lung Cancer Harboring ROS1 Rearrangement1
2RecruitingTreatmentALK Fusion Protein Expression / BRAF wt Allele / Invasive Skin Melanoma / Melanoma / MET Fusion Gene Positive / NRAS wt Allele / NTRK1 Fusion Positive / NTRK2 Fusion Positive / NTRK3 Fusion Positive / RET Fusion Positive / ROS1 Fusion Positive / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IV Cutaneous Melanoma AJCC v6 and v71
2RecruitingTreatmentALK-positive Non-small Cell Lung Cancer / ALK-positive Non-small Cell Lung Cancer (NSCLC) / ALK-positive NSCLC Metastatic to the Brain and/or to Leptomeninges1
2RecruitingTreatmentALK-positive Non-small Cell Lung Cancer1
2RecruitingTreatmentAdenocarcinoma Of Esophagus / Adenocarcinoma of the Pancreas / Cholangiocarcinomas / Colorectal Adenocarcinoma / Gastric Adenocarcinoma / Hepatocellular Adenocarcinoma1
2RecruitingTreatmentAdvanced Melanoma / Melanoma / Unresectable Melanoma1
2RecruitingTreatmentCholangiocarcinomas1
2RecruitingTreatmentLocally Advanced Anaplastic, Undifferentiated Thyroid Cancer / Locally Advanced Anaplastic/Undifferentiated Thyroid Cancer / Metastatic Anaplastic Thyroid Cancer / Metastatic Anaplastic/Undifferentiated Thyroid Cancer1
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2WithdrawnTreatmentMalignancies, Hematologic1
3Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
4RecruitingTreatmentALK Positive Malignancies1
Not AvailableAvailableNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)1
Not AvailableRecruitingNot AvailableAnaplastic Lymphoma Kinase-positive / Carcinoma Non-small-cell Lung1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral150 mg
CapsuleOral150 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8039474No2011-10-182030-06-29Us
US8703787No2014-04-222032-02-02Us
US8377921No2013-02-192027-11-20Us
US8039479No2011-10-182030-06-29Us
US7893074No2011-02-222026-04-25Us
US9309229No2016-04-122032-01-18Us
US7153964No2006-12-262021-02-26Us
US7964592No2011-06-212027-01-13Us
US8399450No2013-03-192027-11-20Us
US8835430No2014-09-162023-01-31Us
US9018204No2015-04-282023-01-31Us
US8188276No2012-05-292023-01-31Us
US9416112No2016-08-162023-01-31Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa9.7 and 4.1FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.00222 mg/mLALOGPS
logP5.23ALOGPS
logP5.81ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)11.58ChemAxon
pKa (Strongest Basic)10.07ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area105.24 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity153.86 m3·mol-1ChemAxon
Polarizability61.33 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Phenylpiperidines
Direct Parent
Phenylpiperidines
Alternative Parents
Benzenesulfonyl compounds / Phenoxy compounds / Phenol ethers / Aniline and substituted anilines / Toluenes / Alkyl aryl ethers / Aminopyrimidines and derivatives / Aralkylamines / Halopyrimidines / Imidolactams
show 9 more
Substituents
Phenylpiperidine / Benzenesulfonyl group / Phenoxy compound / Phenol ether / Aniline or substituted anilines / Alkyl aryl ether / Aminopyrimidine / Halopyrimidine / Toluene / Aralkylamine
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis a...
Gene Name
ALK
Uniprot ID
Q9UM73
Uniprot Name
ALK tyrosine kinase receptor
Molecular Weight
176440.535 Da
References
  1. Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, Wan Y, Ding P, Liu Y, Sun F, Schultz PG, Gray NS, Warmuth M: Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. Epub 2006 Dec 21. [PubMed:17185414]
  2. Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26. [PubMed:23742252]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on May 11, 2015 16:20 / Updated on December 12, 2018 07:19