U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C21H22Cl2FN5O
Molecular Weight 450.3373
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of CRIZOTINIB

SMILES

C[C@]([H])(c1c(ccc(c1Cl)F)Cl)Oc2cc(cnc2N)-c3cnn(c3)C4CCNCC4

InChI

InChIKey=KTEIFNKAUNYNJU-GFCCVEGCSA-N
InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1

HIDE SMILES / InChI

Description
Curator's Comment:: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202570s006lbl.pdf; https://www.mskcc.org/cancer-care/clinical-trials/14-063

(S)-crizotinib was discovered as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 as a promising novel class of anticancer agents.

CNS Activity

Curator's Comment:: The CNS is frequently a site of disease progression, where up to 60% of patients develop metastases during treatment with crizotinib.The most likely reason for such isolated CNS failure is incomplete penetration of the blood-brain barrier by crizotinib.

Originator

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
24.0 nM [IC50]
11.0 nM [IC50]
Target ID: P36639
Gene ID: 4521.0
Gene Symbol: NUDT1
Target Organism: Homo sapiens (Human)
72.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
XALKORI

Approved Use

Indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Launch Date

1.31431675E12
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
475 ng/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
CRIZOTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
99.6 ng/mL
250 mg single, oral
dose: 250 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CRIZOTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
328 ng/mL
250 mg 2 times / day steady-state, oral
dose: 250 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
CRIZOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
327 ng/mL
250 mg 2 times / day multiple, oral
dose: 250 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
CRIZOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
87 ng/mL
250 mg single, oral
dose: 250 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CRIZOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
3240 ng × h/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
CRIZOTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
2321 ng × h/mL
250 mg single, oral
dose: 250 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CRIZOTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
3054 ng × h/mL
250 mg 2 times / day steady-state, oral
dose: 250 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
CRIZOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
3084 ng × h/mL
250 mg 2 times / day multiple, oral
dose: 250 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
CRIZOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1817 ng × h/mL
250 mg single, oral
dose: 250 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CRIZOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
29 h
250 mg single, oral
dose: 250 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CRIZOTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
47.1 h
250 mg single, oral
dose: 250 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
CRIZOTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
9.3%
CRIZOTINIB plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
300 mg 2 times / day steady, oral
Dose: 300 mg, 2 times / day
Route: oral
Route: steady
Dose: 300 mg, 2 times / day
Sources:
unhealthy, 49 years
n = 6
Health Status: unhealthy
Age Group: 49 years
Sex: M+F
Population Size: 6
Sources:
Disc. AE: Fatigue...
AEs leading to
discontinuation/dose reduction:
Fatigue (grade 3, 1 patient)
Sources:
250 mg 2 times / day steady, oral
Recommended|MTD
Dose: 250 mg, 2 times / day
Route: oral
Route: steady
Dose: 250 mg, 2 times / day
Sources:
unhealthy, 51 years (range: 21-79 years)
n = 119
Health Status: unhealthy
Condition: Adenocarcinoma | Squamous Cell Carcinoma |Non-small Cell Lung Cancer
Age Group: 51 years (range: 21-79 years)
Sex: M+F
Population Size: 119
Sources:
Disc. AE: Autoimmune thyroiditis...
AEs leading to
discontinuation/dose reduction:
Autoimmune thyroiditis (1 patient)
Sources:
250 mg 2 times / day steady, oral
Recommended|MTD
Dose: 250 mg, 2 times / day
Route: oral
Route: steady
Dose: 250 mg, 2 times / day
Sources:
unhealthy, 52 years (range: 29-82 years)
n = 136
Health Status: unhealthy
Condition: Adenocarcinoma | Adenosquamous Carcinoma|Non-small Cell Lung Cancer
Age Group: 52 years (range: 29-82 years)
Sex: M+F
Population Size: 136
Sources:
Disc. AE: ALT increased, Pneumonitis...
AEs leading to
discontinuation/dose reduction:
ALT increased (2.2%)
Pneumonitis (1.5%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Fatigue grade 3, 1 patient
Disc. AE
300 mg 2 times / day steady, oral
Dose: 300 mg, 2 times / day
Route: oral
Route: steady
Dose: 300 mg, 2 times / day
Sources:
unhealthy, 49 years
n = 6
Health Status: unhealthy
Age Group: 49 years
Sex: M+F
Population Size: 6
Sources:
Autoimmune thyroiditis 1 patient
Disc. AE
250 mg 2 times / day steady, oral
Recommended|MTD
Dose: 250 mg, 2 times / day
Route: oral
Route: steady
Dose: 250 mg, 2 times / day
Sources:
unhealthy, 51 years (range: 21-79 years)
n = 119
Health Status: unhealthy
Condition: Adenocarcinoma | Squamous Cell Carcinoma |Non-small Cell Lung Cancer
Age Group: 51 years (range: 21-79 years)
Sex: M+F
Population Size: 119
Sources:
Pneumonitis 1.5%
Disc. AE
250 mg 2 times / day steady, oral
Recommended|MTD
Dose: 250 mg, 2 times / day
Route: oral
Route: steady
Dose: 250 mg, 2 times / day
Sources:
unhealthy, 52 years (range: 29-82 years)
n = 136
Health Status: unhealthy
Condition: Adenocarcinoma | Adenosquamous Carcinoma|Non-small Cell Lung Cancer
Age Group: 52 years (range: 29-82 years)
Sex: M+F
Population Size: 136
Sources:
ALT increased 2.2%
Disc. AE
250 mg 2 times / day steady, oral
Recommended|MTD
Dose: 250 mg, 2 times / day
Route: oral
Route: steady
Dose: 250 mg, 2 times / day
Sources:
unhealthy, 52 years (range: 29-82 years)
n = 136
Health Status: unhealthy
Condition: Adenocarcinoma | Adenosquamous Carcinoma|Non-small Cell Lung Cancer
Age Group: 52 years (range: 29-82 years)
Sex: M+F
Population Size: 136
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
weak [IC50 44 uM]
weak [IC50 48 uM]
weak [Inhibition 30 uM]
yes [IC50 0.83 uM]
yes [IC50 14.6 uM]
yes [IC50 22 uM]
yes [IC50 23 uM]
yes [IC50 5.79 uM]
yes [IC50 7.3 uM]
yes (co-administration study)
Comment: crizotinib increased AUC of midazolam by 3.7x
yes [IC50 >30 uM]
yes [IC50 >30 uM]
yes [IC50 >30 uM]
yes [IC50 >30 uM]
yes
no (co-administration study)
Drug as victimTox targets
PubMed

PubMed

TitleDatePubMed
An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.
2007 May 1
[Following communications made at American Society of Clinical Oncology 2010, what will change our practice? The point of view of the editorial board of Bulletin du Cancer].
2010 Dec
New drugs in advanced non-small-cell lung cancer: searching for the correct clinical development.
2010 Dec
ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time.
2010 Dec 14
The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.
2010 Dec 15
Deciding priorities in Pharma.
2010 Dec 20
Exciting new targets in lung cancer therapy: ALK, IGF-1R, HDAC, and Hh.
2010 Jun
Gender specific drug metabolism of PF-02341066 in rats--role of sulfoconjugation.
2010 May
Crizotinib--latest champion in the cancer wars?
2010 Oct 28
EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
2010 Oct 28
Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor.
2010 Oct 28
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
2010 Oct 28
Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen.
2011 Dec
ALK mutations conferring differential resistance to structurally diverse ALK inhibitors.
2011 Dec 1
Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities.
2011 May
Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification.
2011 May
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
2011 May 3
9-substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as highly selective and potent anaplastic lymphoma kinase inhibitors.
2011 Sep 22
Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).
2011 Sep 22
Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma.
2012 Apr
Adenocarcinoma of the lung with miliary brain and pulmonary metastases with echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase translocation treated with crizotinib: a case report.
2012 Dec
Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor.
2012 Jan 20
Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification.
2012 Jul
Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells.
2012 Jul 1
The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma.
2012 Jul 10
ROS1 rearrangements define a unique molecular class of lung cancers.
2012 Mar 10
ALK inhibitor crizotinib combined with intrathecal methotrexate treatment for non-small cell lung cancer with leptomeningeal carcinomatosis.
2012 May
Targeted therapy for lung cancer.
2012 Nov
Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer.
2012 Nov 1
Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma.
2012 Nov 15
Targeting ALK: a promising strategy for the treatment of non-small cell lung cancer, non-Hodgkin's lymphoma, and neuroblastoma.
2012 Sep
Identifying and targeting ROS1 gene fusions in non-small cell lung cancer.
2012 Sep 1
Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants.
2012 Sep 1
Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer.
2013
Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC).
2013 May
Patents

Sample Use Guides

The recommended dose and schedule for crizotinib is 250 mg orally, twice daily, with or without food.
Route of Administration: fVal
PF-2341066 potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC50 value of 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of >120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells at IC50 values of approximately 30 nmol/L but not ALK-negative lymphoma cells.
Name Type Language
CRIZOTINIB
DASH   INN   MART.   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
CRIZOTINIB [USAN]
Common Name English
CRIZOTINIB [JAN]
Common Name English
CRIZOTINIB [ORANGE BOOK]
Common Name English
CRIZOTINIB [MI]
Common Name English
(R)-3-(1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
Systematic Name English
PF-02341066
Code English
CRIZOTINIB [WHO-DD]
Common Name English
2-PYRIDINAMINE, 3-((1R)-1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY)-5-(1-(4-PIPERIDINYL)-1H-PYRAZOL-4-YL)-
Systematic Name English
NSC-756645
Code English
3-((1R)-1-(2,6-DICHLORO-3-FLUOROPHENYL)ETHOXY)-5-(1-(PIPERIDIN-4-YL)-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE
Systematic Name English
CRIZOTINIB [MART.]
Common Name English
CRIZOTINIB [VANDF]
Common Name English
1066
Code English
PF-2341066
Common Name English
XALKORI
Brand Name English
CRIZOTINIB [INN]
Common Name English
Classification Tree Code System Code
WHO-VATC QL01XE16
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
FDA ORPHAN DRUG 379812
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
WHO-ATC L01XE16
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
FDA ORPHAN DRUG 310610
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
FDA ORPHAN DRUG 379712
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
NDF-RT N0000175605
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
NCI_THESAURUS C141136
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
LIVERTOX 241
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
NCI_THESAURUS C129825
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
Code System Code Type Description
MERCK INDEX
M3847
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY Merck Index
DRUG BANK
DB08865
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PRIMARY
ChEMBL
CHEMBL601719
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PRIMARY
NDF-RT
N0000182139
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY Cytochrome P450 2B6 Inhibitors [MoA]
IUPHAR
4903
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
CAS
877399-52-5
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
NDF-RT
N0000185503
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY P-Glycoprotein Inhibitors [MoA]
LACTMED
Crizotinib
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
EVMPD
SUB32267
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
NDF-RT
N0000190114
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY Cytochrome P450 3A Inhibitors [MoA]
JAPANESE REVIEW
XALKORI
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY APPROVED MARCH 2012
INN
9301
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
NDF-RT
N0000191265
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY Organic Cation Transporter 1 Inhibitors [MoA]
NDF-RT
N0000187061
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY Organic Cation Transporter 2 Inhibitors [MoA]
NCI_THESAURUS
C74061
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
MESH
C551994
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
NDF-RT
N0000020000
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY Receptor Tyrosine Kinase Inhibitors [MoA]
PUBCHEM
11626560
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
RXCUI
1148495
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY RxNorm
DRUG CENTRAL
4187
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
FDA UNII
53AH36668S
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY
WIKIPEDIA
CRIZOTINIB
Created by admin on Fri Jun 25 21:49:17 UTC 2021 , Edited by admin on Fri Jun 25 21:49:17 UTC 2021
PRIMARY