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

Details

Stereochemistry ABSOLUTE
Molecular Formula C21H22Cl2FN5O.ClH
Molecular Weight 486.798
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of Crizotinib hydrochloride

SMILES

Cl.C[C@@H](OC1=CC(=CN=C1N)C2=CN(N=C2)C3CCNCC3)C4=C(Cl)C=CC(F)=C4Cl

InChI

InChIKey=BTDNHKQCPIBABF-UTONKHPSSA-N
InChI=1S/C21H22Cl2FN5O.ClH/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);1H/t12-;/m1./s1

HIDE SMILES / InChI

Molecular Formula C21H22Cl2FN5O
Molecular Weight 450.337
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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

2011
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
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
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
Targeted therapies and other agents as first-line maintenance and beyond: particular benefit in pulmonary adenocarcinoma patients.
2011
Synthesis and c-Met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines: identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent.
2011 Apr 14
Favorable response to crizotinib in three patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type oncogene-positive non-small cell lung cancer.
2011 Aug
Synthesis of an aryloxy oxo pyrimidinone library that displays ALK-selective inhibition.
2011 Aug 1
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
Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors.
2011 Feb 1
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
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.
2011 Sep 15
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012 Feb 8
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
Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein.
2012 Jul
Remarkable tumor response to crizotinib in a 14-year-old girl with ALK-positive non-small-cell lung cancer.
2012 Jun 1
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
2012 Mar 1
ROS1 rearrangements define a unique molecular class of lung cancers.
2012 Mar 10
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
Correlations between the percentage of tumor cells showing an anaplastic lymphoma kinase (ALK) gene rearrangement, ALK signal copy number, and response to crizotinib therapy in ALK fluorescence in situ hybridization-positive nonsmall cell lung cancer.
2012 Sep 15
Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer.
2013
Prediction of crizotinib-midazolam interaction using the Simcyp population-based simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes.
2013 Feb
Overcoming erlotinib resistance with tailored treatment regimen in patient-derived xenografts from naïve Asian NSCLC patients.
2013 Jan 15
Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC).
2013 May
Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.
2014 Apr 10
Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects.
2015 Jan 5
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.
Substance Class Chemical
Created
by admin
on Sat Dec 16 20:18:38 GMT 2023
Edited
by admin
on Sat Dec 16 20:18:38 GMT 2023
Record UNII
Z63P44CE4Z
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
Crizotinib hydrochloride
Common Name English
2-Pyridinamine, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-, hydrochloride (1:1)
Systematic Name English
[3-[[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]oxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-yl]amine hydrochloride
Systematic Name English
Code System Code Type Description
FDA UNII
Z63P44CE4Z
Created by admin on Sat Dec 16 20:18:38 GMT 2023 , Edited by admin on Sat Dec 16 20:18:38 GMT 2023
PRIMARY
CAS
1415560-69-8
Created by admin on Sat Dec 16 20:18:38 GMT 2023 , Edited by admin on Sat Dec 16 20:18:38 GMT 2023
PRIMARY
PUBCHEM
71576688
Created by admin on Sat Dec 16 20:18:38 GMT 2023 , Edited by admin on Sat Dec 16 20:18:38 GMT 2023
PRIMARY
Related Record Type Details
PARENT -> SALT/SOLVATE
Related Record Type Details
ACTIVE MOIETY