Dacomitinib
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Identification
- Summary
Dacomitinib is a medication used to treat non small cell lung cancer with EGFR exon 19 deletion of exon 21 L858R substitution.
- Brand Names
- Vizimpro
- Generic Name
- Dacomitinib
- DrugBank Accession Number
- DB11963
- Background
Dacomitinib, designed as (2E)-N-16-4-(piperidin-1-yl) but-2-enamide, is an oral highly selective quinazalone part of the second-generation tyrosine kinase inhibitors which are characterized by the irreversible binding at the ATP domain of the epidermal growth factor receptor family kinase domains.2
Dacomitinib was developed by Pfizer Inc and approved by the FDA on September 27, 2018.14 Some evidence in the literature suggests the therapeutic potential of dacomitinib in the epithelial ovarian cancer model1, although further investigations are needed.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 469.939
Monoisotopic: 469.168080981 - Chemical Formula
- C24H25ClFN5O2
- Synonyms
- Dacomitinib
- Dacomitinib anhydrous
- Dacomitinibum
- External IDs
- PF-00299804
Pharmacology
- Indication
Dacomitinib is indicated as the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as verified by an FDA-approved test.15
Lung cancer is the leading cause of cancer death and NSCLC accounts for 85% of lung cancer cases. From the cases of NSCLC, approximately 75% of the patients present a late diagnosis with metastatic and advanced disease which produces a survival rate of 5%. The presence of a mutation in EGFR accounts for more than the 60% of the NSCLC cases and the overexpression of EGFR is associated with frequent lymph node metastasis and poor chemosensitivity.10,11
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 •••••••••••• •••• •••• •• •••••••• ••••••••• ••••• •••••••• •• •••• •• ••••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Preclinical data suggested that dacomitinib increases the inhibition of the epidermal growth factor receptor kinase domain as well as the activity in cell lines harboring resistance mutations such as T790M. This activity further produced a significant reduction of EGFR phosphorylation and cell viability. In these studies, non-small cell lymphoma cancer cell lines with L858R/T790M mutations where used and an IC50 of about 280 nmol/L was observed.3
In clinical trials with patients with advanced non-small cell lung carcinoma who progressed after chemotherapy, there was an objective response rate of 5% with a progression-free survival of 2.8 months and an overall survival of 9.5 months. As well, phase I/II studies showed positive dacomitinib activity despite prior failure with tyrosine kinase inhibitors.2
Phase III clinical trials (ARCHER 1050), done in patients suffering from advanced or metastatic non-small cell lung carcinoma with EGFR-activating mutations, reported a significant improvement in progression-free survival when compared with gefitinib.8
- Mechanism of action
Dacomitinib is an irreversible small molecule inhibitor of the activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) tyrosine kinases. It achieves irreversible inhibition via covalent bonding to the cysteine residues in the catalytic domains of the HER receptors.4 The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L.2
The ErbB or epidermal growth factor (EGF) family plays a role in tumor growth, metastasis, and treatment resistance by activating downstream signal transduction pathways such as such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K/AKT through the tyrosine kinase-driven phosphorylation at the carboxy-terminus.1 Around 40% of cases show amplification of EGFR gene and 50% of the cases present the EGFRvIII mutation which represents a deletion that produces a continuous activation of the tyrosine kinase domain of the receptor.9
Target Actions Organism AReceptor tyrosine-protein kinase erbB-4 antagonistHumans AReceptor tyrosine-protein kinase erbB-2 antagonistHumans AEpidermal growth factor receptor inhibitorHumans - Absorption
Dacomitinib has shown a linear kinetics after single and multiple dose range studies. The absorption and distribution do not seem to be affected by food or the consumption of antacids. The peak plasma concentration after a dosage of 45 mg for 4 days is of 104 ng/ml.5 The reported AUC0-24h and tmax are of 2213 ng.h/mL and 6 hours, respectively. As well, following oral administration, the absolute oral bioavailability is 80% Label.
- Volume of distribution
The volume of distribution of dacomitinib was reported to be of 2415 L.12
- Protein binding
Dacomitinib is known to present a protein binding of 98%.13
- Metabolism
Dacomitinib presents an oxidative and conjugative metabolism marked mainly by the activity of glutathione and cytochrome P450 enzymes.5 After metabolism, its major circulating metabolite is an O-desmethyl dacomitinib form named PF-05199265.7 This metabolite has been shown to be formed by an oxidative step by CYP2D6 and to a smaller extent by CYP2C9. The following steps of the metabolism are mainly mediated by CYP3A4 for the formation of smaller metabolites.12
From these metabolic studies, it was shown that dacomitinib inhibited strongly the activities of CYP2D6.6
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- Route of elimination
From the administered dose, 79% is recovered in feces, from which 20% represents the unmodified form of dacomitinib, and 3% is recovered in urine, from which <1% is represented by the unchanged form.12
- Half-life
Dacomitinib is reported to have a very large half-life of 70 hours.13
- Clearance
The geometric apparent clearance of dacomitinib is 27.06 L/h.12
- 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 asymptomatic dose in rats was 50 mg/kg MSDS. In animal studies, dacomitinib was shown to induce embryo-fetal toxicity, as demonstrated by an increased incidence of a post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45mg human dose following administration in rats during the period of organogenesis. On the other hand, dacomitinib was showed to lack a mutagenic potential in a bacterial reverse mutation assay, in human lymphocyte chromosome aberration assay and in clastogenic or aneugenic in vivo rat bone marrow micronucleus assay.Label
The dose-limiting and overdose toxicities include stomatitis, rash, palmar-plantar erythrodysesthesia syndrome, dehydration, paronychia, and diarrhea. From these findings, the maximum tolerated dose (defined by the dose in which the dose-limiting toxicities did not exceed 33%) is 45 mg.5
- 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 softwareAbacavir The metabolism of Abacavir can be decreased when combined with Dacomitinib. Abametapir The serum concentration of Dacomitinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Dacomitinib can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Dacomitinib. Abiraterone The metabolism of Dacomitinib can be decreased when combined with Abiraterone. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of dacomitinib.
- Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dacomitinib.
- Take at the same time every day.
- Take separate from antacids. Take dacomitinib at least 6 hours before or 10 hours after administering antacids.
- Take with or without food.
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.
- Product Ingredients
Ingredient UNII CAS InChI Key Dacomitinib monohydrate 5092U85G58 1042385-75-0 BSPLGGCPNTZPIH-IPZCTEOASA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vizimpro Tablet, film coated 15 mg Oral Pfizer Europe Ma Eeig 2020-12-16 Not applicable EU Vizimpro Tablet 15 mg Oral Pfizer Italia S.R.L. 2019-04-22 2021-11-24 Canada Vizimpro Tablet, film coated 15 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2018-10-04 Not applicable US Vizimpro Tablet, film coated 45 mg Oral Pfizer Europe Ma Eeig 2020-12-16 Not applicable EU Vizimpro Tablet 45 mg Oral Pfizer Italia S.R.L. 2019-04-22 2022-06-09 Canada
Categories
- ATC Codes
- L01EB07 — Dacomitinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (strong)
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP2D6 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
- Heterocyclic Compounds, Fused-Ring
- Kinase Inhibitor
- Narrow Therapeutic Index Drugs
- OCT1 inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Protein Kinase Inhibitors
- Quinazolines
- Tyrosine Kinase Inhibitors
- UGT1A1 Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazanaphthalenes
- Sub Class
- Benzodiazines
- Direct Parent
- Quinazolinamines
- Alternative Parents
- Methoxyanilines / N-arylamides / Anisoles / Chlorobenzenes / Fluorobenzenes / Aminopyrimidines and derivatives / Alkyl aryl ethers / Imidolactams / Aryl chlorides / Aryl fluorides show 13 more
- Substituents
- Alkyl aryl ether / Amine / Amino acid or derivatives / Aminopyrimidine / Aniline or substituted anilines / Anisole / Aromatic heteropolycyclic compound / Aryl chloride / Aryl fluoride / Aryl halide show 31 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 2XJX250C20
- CAS number
- 1110813-31-4
- InChI Key
- LVXJQMNHJWSHET-AATRIKPKSA-N
- InChI
- InChI=1S/C24H25ClFN5O2/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29)/b6-5+
- IUPAC Name
- (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide
- SMILES
- COC1=C(NC(=O)\C=C\CN2CCCCC2)C=C2C(NC3=CC(Cl)=C(F)C=C3)=NC=NC2=C1
References
- General References
- Momeny M, Zarrinrad G, Moghaddaskho F, Poursheikhani A, Sankanian G, Zaghal A, Mirshahvaladi S, Esmaeili F, Eyvani H, Barghi F, Sabourinejad Z, Alishahi Z, Yousefi H, Ghasemi R, Dardaei L, Bashash D, Chahardouli B, Dehpour AR, Tavakkoly-Bazzaz J, Alimoghaddam K, Ghavamzadeh A, Ghaffari SH: Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells. Sci Rep. 2017 Jun 23;7(1):4204. doi: 10.1038/s41598-017-04147-0. [Article]
- Brzezniak C, Carter CA, Giaccone G: Dacomitinib, a new therapy for the treatment of non-small cell lung cancer. Expert Opin Pharmacother. 2013 Feb;14(2):247-53. doi: 10.1517/14656566.2013.758714. Epub 2013 Jan 7. [Article]
- Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, Gandhi L, Shapiro GI, Nelson JM, Heymach JV, Meyerson M, Wong KK, Janne PA: PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007 Dec 15;67(24):11924-32. doi: 10.1158/0008-5472.CAN-07-1885. [Article]
- Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM: Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12022-7. [Article]
- Janne PA, Boss DS, Camidge DR, Britten CD, Engelman JA, Garon EB, Guo F, Wong S, Liang J, Letrent S, Millham R, Taylor I, Eckhardt SG, Schellens JH: Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011 Mar 1;17(5):1131-9. doi: 10.1158/1078-0432.CCR-10-1220. Epub 2011 Jan 10. [Article]
- Bello CL, LaBadie RR, Ni G, Boutros T, McCormick C, Ndongo MN: The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers. Cancer Chemother Pharmacol. 2012 Apr;69(4):991-7. doi: 10.1007/s00280-011-1793-7. Epub 2011 Dec 7. [Article]
- Sepulveda JM, Sanchez-Gomez P, Vaz Salgado MA, Gargini R, Balana C: Dacomitinib: an investigational drug for the treatment of glioblastoma. Expert Opin Investig Drugs. 2018 Oct;27(10):823-829. doi: 10.1080/13543784.2018.1528225. Epub 2018 Oct 5. [Article]
- Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS: Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. doi: 10.1016/S1470-2045(17)30608-3. Epub 2017 Sep 25. [Article]
- Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005 Nov 10;353(19):2012-24. doi: 10.1056/NEJMoa051918. [Article]
- da Cunha Santos G, Shepherd FA, Tsao MS: EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. doi: 10.1146/annurev-pathol-011110-130206. [Article]
- Bethune G, Bethune D, Ridgway N, Xu Z: Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010 Mar;2(1):48-51. [Article]
- Chen X, Jiang J, Giri N, Hu P: Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6. Xenobiotica. 2018 May;48(5):459-466. doi: 10.1080/00498254.2017.1342881. Epub 2017 Aug 18. [Article]
- Bethesda (2006). Drugs and Lactation Database. National Library of Medicine.
- FDA approval [Link]
- FDA news [Link]
- Pfizer Oncology Dacomitinib (PF-00299804) Fact Sheet [File]
- External Links
- KEGG Drug
- D09883
- PubChem Compound
- 11511120
- PubChem Substance
- 347828287
- ChemSpider
- 9685914
- BindingDB
- 112499
- 2058848
- ChEBI
- 132268
- ChEMBL
- CHEMBL2110732
- ZINC
- ZINC000072266312
- PDBe Ligand
- 1C9
- Wikipedia
- Dacomitinib
- PDB Entries
- 4i23 / 4i24
- FDA label
- Download (744 KB)
- MSDS
- Download (57.4 KB)
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 Active Not Recruiting Not Available EGFR Mutation-positive Inoperable or Reccrent NSCLC 1 somestatus stop reason just information to hide Not Available Completed Not Available Lung Cancer 1 somestatus stop reason just information to hide Not Available Completed Not Available Non-Small Cell Lung Cancer (NSCLC) 1 somestatus stop reason just information to hide Not Available Completed Diagnostic Squamous Cell Carcinoma of the Head and Neck (SCCHN) 1 somestatus stop reason just information to hide Not Available Enrolling by Invitation Not Available Lung Neoplasm 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 15.576 MG Tablet, film coated Oral 31.153 MG Tablet, film coated Oral 46.729 MG Tablet Oral 15 mg Tablet Oral 30 mg Tablet Oral 45 mg Tablet, film coated Oral 15 mg/1 Tablet, film coated Oral 30 mg/1 Tablet, film coated Oral 45 mg/1 Tablet, film coated Oral Tablet, film coated Oral 15 mg Tablet, film coated Oral 30 mg Tablet, film coated Oral 45 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8623883 No 2014-01-07 2025-05-05 US US7772243 No 2010-08-10 2028-08-26 US US10603314 No 2020-03-31 2026-02-02 US US10596162 No 2020-03-24 2026-02-02 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 184-187 ºC Williams J., et al. (2014). Canc. Treatment Rev. 40, 917. boiling point (°C) 665.7 ºC at 760 mmHg 'MSDS' water solubility <1 mg/mL 'MSDS' logP 3.92 'MSDS' - Predicted Properties
Property Value Source Water Solubility 0.00874 mg/mL ALOGPS logP 4.88 ALOGPS logP 4.71 Chemaxon logS -4.7 ALOGPS pKa (Strongest Acidic) 12.5 Chemaxon pKa (Strongest Basic) 8.55 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 79.38 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 129.91 m3·mol-1 Chemaxon Polarizability 49.06 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 Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-1000900000-111dc0928806f1086f0c Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0103900000-88b1e6bd02e1d931dbd5 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-2105900000-d1d51bc9f539ab4bbcdf Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0296-1106900000-f79ca399cad79342d19a Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0fka-7819500000-619b6593e155c275fa07 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9103600000-b4f47f96fb9dfbc02aff Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 214.83841 predictedDeepCCS 1.0 (2019) [M+H]+ 217.23398 predictedDeepCCS 1.0 (2019) [M+Na]+ 223.14651 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis
- Specific Function
- ATP binding
- Gene Name
- ERBB4
- Uniprot ID
- Q15303
- Uniprot Name
- Receptor tyrosine-protein kinase erbB-4
- Molecular Weight
- 146806.865 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization
- Specific Function
- ATP binding
- Gene Name
- ERBB2
- Uniprot ID
- P04626
- Uniprot Name
- Receptor tyrosine-protein kinase erbB-2
- Molecular Weight
- 137909.27 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:10805725, PubMed:27153536, PubMed:2790960, PubMed:35538033). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:12297049, PubMed:15611079, PubMed:17909029, PubMed:20837704, PubMed:27153536, PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity)
- Specific Function
- actin filament binding
- Gene Name
- EGFR
- Uniprot ID
- P00533
- Uniprot Name
- Epidermal growth factor receptor
- Molecular Weight
- 134276.185 Da
References
- Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB, Trumpp-Kallmeyer S, Dobrusin EM: Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12022-7. [Article]
- Brzezniak C, Carter CA, Giaccone G: Dacomitinib, a new therapy for the treatment of non-small cell lung cancer. Expert Opin Pharmacother. 2013 Feb;14(2):247-53. doi: 10.1517/14656566.2013.758714. Epub 2013 Jan 7. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- Curator comments
- Coadministration of a single 45 mg oral dose of dacomitinib increased dextromethorphan (a CYP2D6 substrate) Cmax by 9.7-fold and AUClast by 9.6 fold.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, 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) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Bello CL, LaBadie RR, Ni G, Boutros T, McCormick C, Ndongo MN: The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers. Cancer Chemother Pharmacol. 2012 Apr;69(4):991-7. doi: 10.1007/s00280-011-1793-7. Epub 2011 Dec 7. [Article]
- Chen X, Jiang J, Giri N, Hu P: Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6. Xenobiotica. 2018 May;48(5):459-466. doi: 10.1080/00498254.2017.1342881. Epub 2017 Aug 18. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Chen X, Jiang J, Giri N, Hu P: Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6. Xenobiotica. 2018 May;48(5):459-466. doi: 10.1080/00498254.2017.1342881. Epub 2017 Aug 18. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). 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) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Chen X, Jiang J, Giri N, Hu P: Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6. Xenobiotica. 2018 May;48(5):459-466. doi: 10.1080/00498254.2017.1342881. Epub 2017 Aug 18. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- Bethesda (2006). Drugs and Lactation Database. National Library of Medicine.
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:11388889, PubMed:11408531, PubMed:12439218, PubMed:12719534, PubMed:15389554, PubMed:16263091, PubMed:16272756, PubMed:16581093, PubMed:19536068, PubMed:21128598, PubMed:23680637, PubMed:24961373, PubMed:34040533, PubMed:9187257, PubMed:9260930, PubMed:9655880). Functions as a pH- and Na(+)-independent, bidirectional transporter (By similarity). Cation cellular uptake or release is driven by the electrochemical potential (i.e. membrane potential and concentration gradient) and substrate selectivity (By similarity). Hydrophobicity is a major requirement for recognition in polyvalent substrates and inhibitors (By similarity). Primarily expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (By similarity). Most likely functions as an uptake carrier in enterocytes contributing to the intestinal elimination of organic cations from the systemic circulation (PubMed:16263091). Transports endogenous monoamines such as N-1-methylnicotinamide (NMN), guanidine, histamine, neurotransmitters dopamine, serotonin and adrenaline (PubMed:12439218, PubMed:24961373, PubMed:35469921, PubMed:9260930). Also transports natural polyamines such as spermidine, agmatine and putrescine at low affinity, but relatively high turnover (PubMed:21128598). Involved in the hepatic uptake of vitamin B1/thiamine, hence regulating hepatic lipid and energy metabolism (PubMed:24961373). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with lower efficency (PubMed:17460754). Also capable of transporting non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). May contribute to the transport of cationic compounds in testes across the blood-testis-barrier (Probable). Also involved in the uptake of xenobiotics tributylmethylammonium (TBuMA), quinidine, N-methyl-quinine (NMQ), N-methyl-quinidine (NMQD) N-(4,4-azo-n-pentyl)-quinuclidine (APQ), azidoprocainamide methoiodide (AMP), N-(4,4-azo-n-pentyl)-21-deoxyajmalinium (APDA) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:11408531, PubMed:15389554, PubMed:35469921, PubMed:9260930)
- Specific Function
- (R)-carnitine transmembrane transporter activity
- Gene Name
- SLC22A1
- Uniprot ID
- O15245
- Uniprot Name
- Solute carrier family 22 member 1
- Molecular Weight
- 61153.345 Da
References
- Dacomatinib EMA label [Link]
Drug created at October 20, 2016 21:05 / Updated at August 26, 2024 19:24