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
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
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 |
DescriptionSources: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm376058.htm?source=govdelivery&utm_medium=email&utm_source=govdeliveryhttps://www.ncbi.nlm.nih.gov/pubmed/24695225Curator'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
Sources: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm376058.htm?source=govdelivery&utm_medium=email&utm_source=govdeliveryhttps://www.ncbi.nlm.nih.gov/pubmed/24695225
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26628475
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=18089725
Curator's Comment: # Pfizer
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL4247 |
24.0 nM [IC50] | ||
Target ID: CHEMBL3717 |
11.0 nM [IC50] | ||
Target ID: P36639 Gene ID: 4521.0 Gene Symbol: NUDT1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/24695225 |
72.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | XALKORI Approved UseIndicated 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 Date2011 |
|||
Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
475 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31778074 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24990113 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
3240 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31778074 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24990113 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
29 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24990113 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
9.3% |
CRIZOTINIB plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse 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%) Sources: Pneumonitis (1.5%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical 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) Comment: effect is masked by inhibition |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | yes (co-administration study) Comment: ketoconazole increased cmax of crizotinib by 44%, auc by 216% |
|||
major | yes (co-administration study) Comment: ketoconazole increased cmax of crizotinib by 44%, auc by 216% |
|||
minor | ||||
minor | ||||
no | ||||
no | ||||
no | ||||
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
[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 |
|
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 |
|
New drugs in advanced non-small-cell lung cancer: searching for the correct clinical development. | 2010 Dec |
|
Deciding priorities in Pharma. | 2010 Dec 20 |
|
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. | 2010 Nov 24 |
|
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 |
|
Targeted therapies and other agents as first-line maintenance and beyond: particular benefit in pulmonary adenocarcinoma patients. | 2011 |
|
Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. | 2011 Oct |
|
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 |
|
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 |
|
Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. | 2012 Jan 20 |
|
Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. | 2012 Jul |
|
Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer. | 2012 Jul |
|
Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. | 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 |
|
Crizotinib in the treatment of non-small-cell lung cancer. | 2012 Jun |
|
Development of treatment strategies for advanced neuroblastoma. | 2012 Jun |
|
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 |
|
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 |
|
[Cavitating nodules in a 40-year-old non-smoking woman: a very particular tumour]. | 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 |
|
Development and validation of a high-throughput intrinsic ATPase activity assay for the discovery of MEKK2 inhibitors. | 2013 Apr |
|
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 |
|
Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. | 2013 Oct 1 |
|
Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. | 2015 Jan 5 |
Sample Use Guides
The recommended dose and schedule for crizotinib is 250 mg orally, twice daily, with or without food.
Route of Administration:
fVal
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=18089725
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
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admin
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Edited
Sat Dec 16 20:18:38 GMT 2023
by
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Record UNII |
Z63P44CE4Z
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Record Status |
Validated (UNII)
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Record Version |
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