CERITINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H36ClN5O3S
Molecular Weight	558.135
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC(C)OC1=CC(C2CCNCC2)=C(C)C=C1NC3=NC=C(Cl)C(NC4=CC=CC=C4S(=O)(=O)C(C)C)=N3

InChI

InChIKey=VERWOWGGCGHDQE-UHFFFAOYSA-N

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)

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Description

Ceritinib is a selective inhibitor of ALK1, a target found in metastatic non-small cell lung cancer (NSCLC). Ceritinib is approved by FDA and is indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. Ceritinib also targets insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ALK tyrosine kinase receptor 24	Antagonist 2,849		0.15 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer 211	Primary		Approved 8,583	ZYKADIA

C_max

Value	Dose	Co-administered	Analyte	Population
800 ng/mL	750 mg 1 times / day multiple, oral		CERITINIB plasma	Homo sapiens
917 ng/mL	450 mg 1 times / day multiple, oral		CERITINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
16500 ng × h/mL	750 mg 1 times / day multiple, oral		CERITINIB plasma	Homo sapiens
18900 ng × h/mL	450 mg 1 times / day multiple, oral		CERITINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
40 h	750 mg 1 times / day multiple, oral		CERITINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
3%	750 mg 1 times / day multiple, oral		CERITINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)	Disc. AE: Diarrhea...
450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)	Disc. AE: Nausea...
450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)	Other AEs: Vomiting, Abdominal pain...
600 mg 1 times / day steady, oral	unhealthy, 39 years (range: 34–61 years)	DLT: Lipase increased...
750 mg 1 times / day steady, oral MTD	unhealthy, 53 years	Disc. AE: Pneumonitis... Other AEs: Pneumonitis...

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AEs

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AE	Significance	Dose	Population
Diarrhea	all grades, 33% Disc. AE	450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)
Nausea	all grades, 100% Disc. AE	450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)
Maculopapular rash	17%	450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)
Stomatitis	33%	450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)
Vomiting	all grades, 100%	450 mg 1 times / day steady, oral Recommended	unhealthy, 37 years (range: 29–67 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252 inducer 1,087	inhibitor 2,438 inducer 440	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2A6 879 CYP2B6 926 CYP2C19 2,057 CYP2E1 1,060 P-gp 1,741 BCRP 910 OATP1B1 1,079 OATP1B3 961 OAT1 725 OAT3 747 OCT2 779 OCT1 620	CYP3A 220 P-gp 2,052 BCRP 697 OCT1 393 OAT2 125 OATP1B1 503 OATP2B1 122	CYP1A2 832 CYP2B6 669

Drug as perpetrator

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Target	Modality	Activity
BCRP 985	inhibitor 4,027	no
OAT3 749	inhibitor 4,027	no
OCT1 656	inhibitor 4,027	no
P-gp 1,932	inhibitor 4,027	no
CYP3A4 2,633	inhibitor 4,027	yes [IC50 0.2 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A 220	substrate 4,014	major	yes (co-administration study)
OAT2 125	substrate 4,014	no
OATP1B1 503	substrate 4,014	no
OATP2B1 122	substrate 4,014	no
OCT1 393	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:78432	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:78432
ChemicalBook	CB82652832	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB82652832
MolPort	MolPort-035-395-774	https://www.molport.com/shop/molecule-link/MolPort-035-395-774
Selleck Chemicals	ldk378	http://www.selleckchem.com/products/ldk378.html
ZINC	ZINC000096272772	http://zinc15.docking.org/substances/ZINC000096272772

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PubMed

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Title	Date	PubMed
Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.	2007 Jan 2	17185414

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Patents

Sample Use Guides

In Vivo Use Guide

750 mg orally once daily. Administer ZYKADIA on an empty stomach (i.e., do not administer within 2 hours of a meal).

Route of Administration: Oral

In Vitro Use Guide

In vitro Ceritinib inhibited ALK+-NSCLC cell lines (H3112 and H2228) with GIC50 values of 6.3 and 3.8 nM.

Show entries

Name

Type

Language

ceritinib [INN]

Preferred Name

English

CERITINIB

Official Name

English

CERITINIB [MI]

Common Name

English

2,4-PYRIMIDINEDIAMINE, 5-CHLORO-N4-(2-((1-METHYLETHYL)SULFONYL)PHENYL)-N2-(5-METHYL-2-(1-METHYLETHOXY)-4-(4-PIPERIDINYL)PHENYL)-

Systematic Name

English

CERITINIB [ORANGE BOOK]

Common Name

English

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Classification Tree

Code System

Code

Tyrosine Kinase Inhibitor

NCI_THESAURUS

C141136

Protein kinase inhibitors

WHO-ATC

L01XE28

Designated/Approved

FDA ORPHAN DRUG

405213

Established Pharmacologic Class

NDF-RT

N0000175605

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

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Code System

Code

Type

Description

INN

9817

PRIMARY

EU-Orphan Drug

5-chloro-N2-[2-isopropoxy(-5-methyl-4-...(NEGATIVE)

PRIMARY

Treatment of non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive 28/03/2014 Negative

LACTMED

Ceritinib

PRIMARY

NDF-RT

N0000185504

PRIMARY

Cytochrome P450 2C9 Inhibitors [MoA]

NDF-RT

N0000020000

PRIMARY

Receptor Tyrosine Kinase Inhibitors [MoA]

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ACTIVE MOIETY


					K418KG2GET

CERITINIB

METABOLITE (PARENT)


					3Z0UX41907

2-((5-CHLORO-4-((2-(ISOPROPYLSULFONYL)PHENYL)AMINO)PYRIMIDIN-2-YL)AMINO)-4-METHYL-5-(PIPERIDIN-4-YL)PHENOL

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator