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Identification
- Summary
Crizotinib is a receptor tyrosine kinase inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) where the tumors have been confirmed to be anaplastic lymphoma kinase (ALK), or ROS1-positive.
- Brand Names
- Xalkori
- Generic Name
- Crizotinib
- DrugBank Accession Number
- DB08865
- Background
Crizotinib is a tyrosine kinase receptor inhibitor used for the treatment of anaplastic lymphoma kinase (ALK) or ROS1-positive non-small cell lung cancer (NSCLC) tumors, as well as ALK-positive anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT).4 By targeting the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein, crizotinib offers robust effectiveness in treating NSCLC in patients with this type of rearrangement.3 Crizotinib was the first-in-class drug used to treat ALK-positive tumors. Second- and third-generation ALK-tyrosine kinase-inhibitors have overcome many of the pharmacodynamic and genetic resistance mechanisms crizotinib is prone to.3 Crizotinib was approved by the FDA in 2011, and its use is accompanied by FDA-approved tests used to detect ALK and ROS1 rearrangements.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Crizotinib (DB08865)
- Weight
- Average: 450.337
Monoisotopic: 449.11854397 - Chemical Formula
- C21H22Cl2FN5O
- Synonyms
- (R)-crizotinib
- Crizotinib
- Crizotinibum
- External IDs
- 1066
- PF 02341066
- PF 2341066
- PF-02341066
- PF-2341066
Pharmacology
- Indication
Crizotinib is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test.4 Crizotinib is also indicated for the treatment of relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients 1 year of age and older and young adults. The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL.4 Additionally, crizotinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive.4
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Metastatic non-small cell lung cancer •••••••••••• Treatment of Metastatic non-small cell lung cancer •••••••••••• Treatment of Refractory anaplastic large cell lymphoma •••••••••••• ••••••••• Treatment of Recurrent inflammatory myofibroblastic tumors •••••••••••• Treatment of Refractory inflammatory myofibroblastic tumors •••••••••••• - Contraindications & Blackbox Warnings
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In a phase I study, 37 patients with a variety of solid-tumor cancers refractory to therapy received 50 to 300 mg of crizotinib daily or twice daily. In this group, two patients with non-small cell lung cancer (NSCLC) exhibiting echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) mutations responded to therapy; therefore, following studies focused on patients with advanced ALK-positive disease.1 In this group of patients, the 6-month progression-free survival among crizotinib users was approximately 72%. When compared to ALK mutation-positive patients that did not receive crizotinib, ALK mutation-positive patients treated with crizotinib had a higher two-year overall survival rate (54% vs 36%).1
The use of crizotinib may lead to hepatotoxicity, interstitial lung disease (ILD), pneumonitis, QT interval prolongation, bradycardia, severe visual loss, embryo-fetal toxicity and gastrointestinal toxicity in pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumor (IMT).4
- Mechanism of action
Crizotinib is a tyrosine kinase receptor inhibitor that targets anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON).4 When activated, ALK inhibits apoptosis and promotes cell proliferation, and ALK-gene translocations can lead to the expression of oncogenic fusion proteins. A small portion of non-small cell lung cancer (NSCLC) patients have ALK-positive tumors. Most of these cases are characterized by the fusion of ALK with the chimeric protein echinoderm microtubule-associated protein-like 4 (EML4), resulting in increased kinase activity.1,4 Crizotinib inhibits ALK by inhibiting its phosphorylation and creating an inactive protein conformation.3 This ultimately lowers the proliferation of cells carrying this genetic mutation and tumour survivability.4
In vitro assays on tumor cell lines demonstrated that crizotinib inhibits ALK, ROS1, and c-Met phosphorylation in a concentration-dependent manner. In vivo studies in mice with tumor xenografts that expressed EML4- or nucleophosmin (NPM)-ALK fusion proteins or c-Met showed that crizotinib has antitumor activity.4
Target Actions Organism AALK tyrosine kinase receptor inhibitorHumans AHepatocyte growth factor receptor inhibitorHumans AProto-oncogene tyrosine-protein kinase ROS inhibitorHumans AMacrophage-stimulating protein receptor inhibitorHumans - Absorption
In patients with pancreatic, colorectal, sarcoma, anaplastic large-cell lymphoma and non-small cell lung cancer (NSCLC) treated with crizotinib doses ranging from 100 mg once a day to 300 mg twice a day, the mean AUC and Cmax increased in a dose-proportional manner.2 A single crizotinib dose of crizotinib is absorbed with a median tmax 4 to 6 hours.4 In patients receiving multiple doses of crizotinib 250 mg twice daily (n=167), the mean AUC was is 2321.00 ng⋅hr/mL, the mean Cmax was 99.60 ng/mL, and the median tmax was 5.0 hours.1 The mean absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%. High-fat meals reduce the AUC0-INF and Cmax of crizotinib by approximately 14%.4 Age, sex at birth, and ethnicity (Asian vs non-Asian patients) did not have a clinically significant effect on crizotinib pharmacokinetics. In patients less than 18 years old, higher body weight was associated with a lower crizotinib exposure.4
- Volume of distribution
Following a single intravenous dose, the mean volume of distribution (Vss) of crizotinib was 1772 L.4
- Protein binding
Crizotinib is 91% bound to plasma protein. In vitro studies suggest that this is not affected by drug concentration.4
- Metabolism
Crizotinib is mainly metabolized in the liver by CYP3A4 and CYP3A5, and undergoes an O-dealkylation, with subsequent phase 2 conjugation.1 Non-metabolic elimination, such as biliary excretion, can not be excluded.5 PF-06260182 (with two constituent diastereomers, PF-06270079 and PF-06270080) is the only active metabolite of crizotinib that has been identified. In vitro studies suggest that, compared to crizotinib, PF-06270079 and PF-06270080 are approximately 3- to 8-fold less potent against anaplastic lymphoma kinase (ALK) and 2.5- to 4-fold less potent against Hepatocyte Growth Factor Receptor (HGFR, c-Met).5
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- Route of elimination
After administering a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose were recovered in feces and urine. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.4
- Half-life
Following single doses of crizotinib, the plasma terminal half-life was 42 hours.4
- Clearance
At steady-state (250 mg twice daily), crizotinib has a mean apparent clearance (CL/F) of 60 L/hr. This value is lower than the one detected after a single 250 mg oral dose (100 L/hr),4, possibly due to CYP3A auto-inhibition.5
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
The maximum tolerated dose of crizotinib is the same as the recommended dosing regimen (250 mg twice daily). This was defined based on a phase 1 dose-escalation study in patients with advanced solid tumors. The treatment of crizotinib overdoses should consist of symptomatic treatment and other supportive measures. There is no antidote for crizotinib.6 In vitro and in vivo studies have shown that crizotinib is genotoxic, and the Ames test showed that crizotinib was not mutagenic. Carcinogenicity studies with crizotinib have not been performed.4
In female rats, 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) of crizotinib for 3 days induced single-cell necrosis of ovarian follicles. In male rats, 50 mg/kg/day of crizotinib (greater than 1.7 times the recommended human dose) for 28 days induced testicular pachytene spermatocyte degeneration.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Crizotinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Crizotinib can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Crizotinib. Abrocitinib The serum concentration of Crizotinib can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Crizotinib. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of crizotinib.
- Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of crizotinib.
- Take with or without food. High-fat food decreases drug absorption, but not to a clinically significant extent.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Xalkori Capsule 50 mg Oral Pfizer Europe Ma Eeig 2024-10-01 Not applicable EU 
Xalkori Capsule, coated pellets 20 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2023-11-20 Not applicable US 
Xalkori Capsule 250 mg Oral Pfizer Italia S.R.L. 2012-05-10 Not applicable Canada 
Xalkori Capsule 250 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2011-08-26 Not applicable US Xalkori Capsule 20 mg Oral Pfizer Europe Ma Eeig 2024-10-01 Not applicable EU
Categories
- ATC Codes
- L01ED01 — Crizotinib
- Drug Categories
- Aminopyridines
- Anaplastic lymphoma kinase (ALK) inhibitors
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Bradycardia-Causing Agents
- Cytochrome P-450 CYP2B6 Inhibitors
- Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A5 Inhibitors
- Cytochrome P-450 CYP3A5 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 CYP3A5 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Kinase Inhibitor
- Moderate Risk QTc-Prolonging Agents
- Narrow Therapeutic Index Drugs
- OCT2 Inhibitors
- Organic Cation Transporter 1 Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Piperidines
- Protein Kinase Inhibitors
- Pyridines
- QTc Prolonging Agents
- Receptor Tyrosine Kinase Inhibitors
- ROS1 tyrosine kinase inhibitors
- Tyrosine Kinase Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as pyrazolylpyridines. These are compounds containing a pyrazolylpyridine skeleton, which consists of a pyrazole linked (not fused) to a pyridine by a bond.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Pyridines and derivatives
- Sub Class
- Pyrazolylpyridines
- Direct Parent
- Pyrazolylpyridines
- Alternative Parents
- Dichlorobenzenes / Alkyl aryl ethers / Aminopyridines and derivatives / Fluorobenzenes / Piperidines / Aryl chlorides / Aryl fluorides / Imidolactams / Pyrazoles / Heteroaromatic compounds show 7 more
- Substituents
- 1,3-dichlorobenzene / 3-pyrazolylpyridine / Alkyl aryl ether / Amine / Aminopyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle show 23 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)pyrazol-4-yl]pyridin-2-amine (CHEBI:64310)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 53AH36668S
- CAS number
- 877399-52-5
- InChI Key
- KTEIFNKAUNYNJU-GFCCVEGCSA-N
- InChI
- 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
- IUPAC Name
- 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine
- SMILES
- C[C@@H](OC1=CC(=CN=C1N)C1=CN(N=C1)C1CCNCC1)C1=C(Cl)C=CC(F)=C1Cl
References
- Synthesis Reference
Cui, JJ., et al. (2014). Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors (U.S. Patent No. US 8,785,632 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/d5/82/7a/7fec499c2af772/US8785632.pdf
- General References
- Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261. [Article]
- Forde PM, Rudin CM: Crizotinib in the treatment of non-small-cell lung cancer. Expert Opin Pharmacother. 2012 Jun;13(8):1195-201. doi: 10.1517/14656566.2012.688029. [Article]
- Heigener DF, Reck M: Crizotinib. Recent Results Cancer Res. 2018;211:57-65. doi: 10.1007/978-3-319-91442-8_4. [Article]
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
- FDA Clinical Pharmacology and Biopharmaceutics Review: XALKORI (crizotinib) capsules for oral use [Link]
- Health Canada Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
- External Links
- KEGG Drug
- D09731
- PubChem Compound
- 11626560
- PubChem Substance
- 310264901
- ChemSpider
- 9801307
- BindingDB
- 50306682
- 1148495
- ChEBI
- 64310
- ChEMBL
- CHEMBL601719
- ZINC
- ZINC000035902489
- PharmGKB
- PA165946122
- PDBe Ligand
- VGH
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Crizotinib
- PDB Entries
- 2wgj / 2xp2 / 2yfx / 3zbf / 4anq / 4ans / 4c9w / 5aaa / 5aab / 5aac … show 1 more
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available ALK positive Non-Small Cell Lung Cancer (NSCLC) 1 somestatus stop reason just information to hide Not Available Completed Not Available Non-Small Cell Lung Cancer (NSCLC) 3 somestatus stop reason just information to hide Not Available Completed Treatment ALK Phosphorylation 1 somestatus stop reason just information to hide Not Available Completed Treatment Solid Tumors 1 somestatus stop reason just information to hide Not Available No Longer Available Not Available Inflammatory Myofibroblastic Tumors 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 150 mg Capsule Oral 20 mg Capsule Oral 200 mg/1 Capsule Oral 250 mg/1 Capsule Oral 50 mg Capsule, coated pellets Oral 150 mg/1 Capsule, coated pellets Oral 20 mg/1 Capsule, coated pellets Oral 50 mg/1 Capsule, coated Oral 200 mg Capsule, coated Oral 250 mg Capsule Oral 200 mg Capsule Oral 250 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region CA2517256 No 2013-04-30 2024-02-26 Canada CA2577937 No 2010-12-21 2025-08-15 Canada CA2578066 No 2011-10-11 2025-08-15 Canada CA2632286 No 2011-11-15 2026-11-23 Canada US7825137 No 2010-11-02 2027-05-12 US US7858643 No 2010-12-28 2029-10-08 US US7230098 No 2007-06-12 2025-08-26 US US8217057 No 2012-07-10 2029-11-06 US US8785632 No 2014-07-22 2025-03-01 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble FDA Chemistry Review: XALKORI (crizotinib) Capsules. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000ChemR.pdf logP 1.83 EMA Assessment Report: XALKORI (crizotinib) Capsules. Available at https://www.ema.europa.eu/en/documents/variation-report/xalkori-h-c-2489-ii-0039-epar-assessment-report-variation_en.pdf pKa 9.4 and 5.6 FDA Chemistry Review: XALKORI (crizotinib) Capsules. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000ChemR.pdf - Predicted Properties
Property Value Source Water Solubility 0.00611 mg/mL ALOGPS logP 3.82 ALOGPS logP 3.57 Chemaxon logS -4.9 ALOGPS pKa (Strongest Basic) 10.12 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 77.99 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 128.43 m3·mol-1 Chemaxon Polarizability 45.44 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9721 Caco-2 permeable - 0.5672 P-glycoprotein substrate Substrate 0.6938 P-glycoprotein inhibitor I Non-inhibitor 0.6713 P-glycoprotein inhibitor II Inhibitor 0.7105 Renal organic cation transporter Inhibitor 0.5464 CYP450 2C9 substrate Non-substrate 0.7545 CYP450 2D6 substrate Non-substrate 0.7023 CYP450 3A4 substrate Substrate 0.6029 CYP450 1A2 substrate Inhibitor 0.6676 CYP450 2C9 inhibitor Inhibitor 0.5 CYP450 2D6 inhibitor Non-inhibitor 0.8662 CYP450 2C19 inhibitor Inhibitor 0.6237 CYP450 3A4 inhibitor Non-inhibitor 0.6301 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8676 Ames test Non AMES toxic 0.5981 Carcinogenicity Non-carcinogens 0.8018 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.6581 LD50, mol/kg Not applicable hERG inhibition (predictor I) Strong inhibitor 0.643 hERG inhibition (predictor II) Inhibitor 0.7877
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 192.4232 predictedDeepCCS 1.0 (2019) [M+H]+ 194.7812 predictedDeepCCS 1.0 (2019) [M+Na]+ 201.05109 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system (PubMed:11121404, PubMed:11387242, PubMed:16317043, PubMed:17274988, PubMed:30061385, PubMed:34646012, PubMed:34819673). Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response (PubMed:30061385, PubMed:33411331, PubMed:34646012, PubMed:34819673). In contrast, ALKAL1 is not a potent physiological ligand for ALK (PubMed:34646012). Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway (PubMed:34819673). Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif (PubMed:15226403, PubMed:16878150). Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 (PubMed:15226403, PubMed:16878150). ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK) (PubMed:11278720, PubMed:11809760, PubMed:12107166, PubMed:12122009). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation (PubMed:11278720, PubMed:11809760, PubMed:12107166). MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction (PubMed:12122009). Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase (PubMed:15226403, PubMed:16878150). Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK (PubMed:15226403, PubMed:16878150)
- Specific Function
- ATP binding
- Gene Name
- ALK
- Uniprot ID
- Q9UM73
- Uniprot Name
- ALK tyrosine kinase receptor
- Molecular Weight
- 176440.535 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of neuronal precursors, angiogenesis and kidney formation. During skeletal muscle development, it is crucial for the migration of muscle progenitor cells and for the proliferation of secondary myoblasts (By similarity). In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells. May regulate cortical bone osteogenesis (By similarity)
- Specific Function
- ATP binding
- Gene Name
- MET
- Uniprot ID
- P08581
- Uniprot Name
- Hepatocyte growth factor receptor
- Molecular Weight
- 155540.035 Da
References
- Forde PM, Rudin CM: Crizotinib in the treatment of non-small-cell lung cancer. Expert Opin Pharmacother. 2012 Jun;13(8):1195-201. doi: 10.1517/14656566.2012.688029. [Article]
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. NELL2 is an endogenous ligand for ROS1. Upon endogenous stimulation by NELL2, ROS1 activates the intracellular signaling pathway and triggers epididymal epithelial differentiation and subsequent sperm maturation (By similarity). May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2
- Specific Function
- ATP binding
- Gene Name
- ROS1
- Uniprot ID
- P08922
- Uniprot Name
- Proto-oncogene tyrosine-protein kinase ROS
- Molecular Weight
- 263912.88 Da
References
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Also plays a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand
- Specific Function
- ATP binding
- Gene Name
- MST1R
- Uniprot ID
- Q04912
- Uniprot Name
- Macrophage-stimulating protein receptor
- Molecular Weight
- 152240.095 Da
References
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261. [Article]
- Filppula AM, Neuvonen PJ, Backman JT: In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8. [Article]
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
- Specific Function
- aromatase activity
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261. [Article]
- Filppula AM, Neuvonen PJ, Backman JT: In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8. [Article]
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
Components:
| Name | UniProt ID |
|---|---|
| Cytochrome P450 3A4 | P08684 |
| Cytochrome P450 3A43 | Q9HB55 |
| Cytochrome P450 3A5 | P20815 |
| Cytochrome P450 3A7 | P24462 |
References
- Filppula AM, Neuvonen PJ, Backman JT: In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8. [Article]
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Clinical Pharmacology and Biopharmaceutics Review: XALKORI (crizotinib) capsules for oral use [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
Components:
References
- FDA Clinical Pharmacology and Biopharmaceutics Review: XALKORI (crizotinib) capsules for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Zhou WJ, Zhang X, Cheng C, Wang F, Wang XK, Liang YJ, To KK, Zhou W, Huang HB, Fu LW: Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. Br J Pharmacol. 2012 Jul;166(5):1669-83. doi: 10.1111/j.1476-5381.2012.01849.x. [Article]
- FDA Approved Drug Products: XALKORI (crizotinib) capsules for oral use [Link]
Drug created at March 28, 2013 17:22 / Updated at October 29, 2024 14:47