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

Details

Stereochemistry ABSOLUTE
Molecular Formula C21H22Cl2FN5O.C2H4O2
Molecular Weight 510.389
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of Crizotinib acetate

SMILES

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

InChI

InChIKey=LFCVDLCLKZRGFW-UTONKHPSSA-N
InChI=1S/C21H22Cl2FN5O.C2H4O2/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;1-2(3)4/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27);1H3,(H,3,4)/t12-;/m1./s1

HIDE SMILES / InChI

Molecular Formula C2H4O2
Molecular Weight 60.052
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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

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
Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases.
2010 Dec
Trial watch: success for crizotinib in ALK-driven cancer.
2010 Dec
Rapid and dramatic radiographic and clinical response to an ALK inhibitor (crizotinib, PF02341066) in an ALK translocation-positive patient with non-small cell lung cancer.
2010 Dec
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
Targeted therapies and other agents as first-line maintenance and beyond: particular benefit in pulmonary adenocarcinoma patients.
2011
Crizotinib: an anaplastic lymphoma kinase inhibitor.
2011 Aug
Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen.
2011 Dec
Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684.
2011 Dec 15
MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib.
2011 Dec 20
Crizotinib in anaplastic large-cell lymphoma.
2011 Feb 24
Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities.
2011 May
Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma.
2011 Nov 9
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
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
Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells.
2012 Dec 13
ALK fusion gene positive lung cancer and 3 cases treated with an inhibitor for ALK kinase activity.
2012 Jan
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
Development of treatment strategies for advanced neuroblastoma.
2012 Jun
Remarkable tumor response to crizotinib in a 14-year-old girl with ALK-positive non-small-cell lung cancer.
2012 Jun 1
A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK.
2012 Jun 29
Pharmacokinetic/pharmacodynamic modeling of crizotinib for anaplastic lymphoma kinase inhibition and antitumor efficacy in human tumor xenograft mouse models.
2012 Mar
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
2012 Mar 1
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
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
2012 Oct
[Cavitating nodules in a 40-year-old non-smoking woman: a very particular tumour].
2012 Sep
Targeting ALK: a promising strategy for the treatment of non-small cell lung cancer, non-Hodgkin's lymphoma, and neuroblastoma.
2012 Sep
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
Crizotinib for the treatment of non-small-cell lung cancer.
2013 Jun 1
Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC).
2013 May
Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes.
2013 Oct 1
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 11:26:07 GMT 2023
Edited
by admin
on Sat Dec 16 11:26:07 GMT 2023
Record UNII
FB99MH8KWZ
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
Crizotinib acetate
Common 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 monoacetate
Systematic Name English
Acetic acid, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Systematic Name English
2-Pyridinamine, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-, acetate (1:1)
Systematic Name English
2-Pyridinamine, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-yl]-, monoacetate
Systematic Name English
Code System Code Type Description
PUBCHEM
67175389
Created by admin on Sat Dec 16 11:26:07 GMT 2023 , Edited by admin on Sat Dec 16 11:26:07 GMT 2023
PRIMARY
FDA UNII
FB99MH8KWZ
Created by admin on Sat Dec 16 11:26:07 GMT 2023 , Edited by admin on Sat Dec 16 11:26:07 GMT 2023
PRIMARY
CAS
877399-53-6
Created by admin on Sat Dec 16 11:26:07 GMT 2023 , Edited by admin on Sat Dec 16 11:26:07 GMT 2023
PRIMARY
EPA CompTox
DTXSID00236600
Created by admin on Sat Dec 16 11:26:07 GMT 2023 , Edited by admin on Sat Dec 16 11:26:07 GMT 2023
PRIMARY
Related Record Type Details
PARENT -> SALT/SOLVATE
Related Record Type Details
ACTIVE MOIETY