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Dacomitinib

PubChem CID
70693519
Structure
Dacomitinib_small.png
Dacomitinib_3D_Structure.png
Molecular Formula
Synonyms
  • 1042385-75-0
  • Dacomitinib monohydrate
  • DACOMITINIB HYDRATE
  • Vizimpro
  • Dacomitinib (hydrate)
Molecular Weight
488.0 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2013-02-04
  • Modify:
    2025-02-01
Description
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. Dacomitinib was developed by Pfizer Inc and approved by the FDA on September 27, 2018. Some evidence in the literature suggests the therapeutic potential of dacomitinib in the epithelial ovarian cancer model, although further investigations are needed.
Dacomitinib is a multi-kinase receptor inhibitor used in the therapy of cases of non-small cell lung cancer that harbor activating mutations in the epidermal growth factor receptor gene (EGFR). Dacomitinib is associated with high rate of transient serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent acute liver injury.
Dacomitinib is a highly selective, orally bioavailable small-molecule inhibitor of the HER family of tyrosine kinases with potential antineoplastic activity. Dacomitinib specifically and irreversibly binds to and inhibits human Her-1, Her-2, and Her-4, resulting in the proliferation inhibition and apoptosis of tumor cells that overexpress these receptors.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Dacomitinib.png

1.2 3D Conformer

3D Conformer of Parent

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide;hydrate
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C24H25ClFN5O2.H2O/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);1H2/b6-5+;
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

BSPLGGCPNTZPIH-IPZCTEOASA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)NC(=O)/C=C/CN4CCCCC4.O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C24H27ClFN5O3
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

1042385-75-0
1110813-31-4

2.3.2 UNII

2.3.3 ChEMBL ID

2.3.4 DrugBank ID

2.3.5 DSSTox Substance ID

2.3.6 KEGG ID

2.3.7 Metabolomics Workbench ID

2.3.8 NCI Thesaurus Code

2.3.9 Pharos Ligand ID

2.3.10 RXCUI

2.3.11 Wikidata

2.3.12 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • dacomitinib
  • N-(4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl)-4-(1-piperidinyl)-2-butenamide
  • PF 00299804
  • PF-00299804
  • PF00299804
  • Vizimpro

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
488.0 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
8
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
487.1786456 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
487.1786456 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
80.4 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
34
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
665
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
2
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Boiling Point

665.7 ºC at 760 mmHg
'MSDS'

3.2.2 Melting Point

184-187 ºC
Williams J., et al. (2014). Canc. Treatment Rev. 40, 917.

3.2.3 Solubility

<1 mg/mL
'MSDS'

3.2.4 LogP

3.92
'MSDS'

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Antineoplastic Agents; Enzyme Inhibitors; Tyrosine Kinase Inhibitors; Lactation; Breast Feeding;
Human drug -> Prescription
Human drug -> Active ingredient (DACOMITINIB)
Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug 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. 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.
Vizimpro, as monotherapy, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations.

6.2 LiverTox Summary

Dacomitinib is a multi-kinase receptor inhibitor used in the therapy of cases of non-small cell lung cancer that harbor activating mutations in the epidermal growth factor receptor gene (EGFR). Dacomitinib is associated with high rate of transient serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent acute liver injury.

6.3 Drug Classes

Antineoplastic Agents; Enzyme Inhibitors; Tyrosine Kinase Inhibitors; Lactation; Breast Feeding;
Antineoplastic Agents

6.4 FDA Approved Drugs

6.5 FDA Orange Book

6.6 FDA National Drug Code Directory

6.7 Drug Labels

Drug and label
Active ingredient and drug

6.8 Cancer Drugs

Drug Name
Dacomitinib
Brand Name(s)
Vizimpro
FDA Approved
Yes
Drug Use

Dacomitinib is approved to treat:

• Non-small cell lung cancer (NSCLC) that has metastasized (spread to other parts of the body). It is used as first-line treatment in patients whose tumors have certain EGFRgenemutations.

Dacomitinib is also being studied in the treatment of other types of cancer.

6.9 Clinical Trials

6.9.1 ClinicalTrials.gov

6.9.2 EU Clinical Trials Register

6.10 EMA Drug Information

Medicine
Category
Human drugs
Therapeutic area
Carcinoma, Non-Small-Cell Lung
Active Substance
dacomitinib monohydrate
INN/Common name
dacomitinib
Pharmacotherapeutic Classes
Antineoplastic agents
Status
This medicine is authorized for use in the European Union
Company
Pfizer Europe MA EEIG
Market Date
2019-04-02

6.11 Japan PMDA Drugs

Brand Name
Vizimpro
Non-proprietary Name
Dacomitinib hydrate
Approval Date
January 2019
Review Document

7 Pharmacology and Biochemistry

7.1 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. 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. 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.

7.2 MeSH Pharmacological Classification

Tyrosine Kinase Inhibitors
Protein kinase inhibitors that inhibit TYROSINE PROTEIN KINASES. (See all compounds classified as Tyrosine Kinase Inhibitors.)

7.3 ATC Code

L01EB07

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EB - Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors

L01EB07 - Dacomitinib

7.4 Absorption, Distribution and Excretion

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. 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%.
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.
Volume of Distribution
The volume of distribution of dacomitinib was reported to be of 2415 L.
Clearance
The geometric apparent clearance of dacomitinib is 27.06 L/h.

7.5 Metabolism / Metabolites

Dacomitinib presents an oxidative and conjugative metabolism marked mainly by the activity of glutathione and cytochrome P450 enzymes. After metabolism, its major circulating metabolite is an O-desmethyl dacomitinib form named PF-05199265. 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. From these metabolic studies, it was shown that dacomitinib inhibited strongly the activities of CYP2D6.

7.6 Biological Half-Life

Dacomitinib is reported to have a very large half-life of 70 hours.

7.7 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. The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L. 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. 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.

8 Use and Manufacturing

8.1 Uses

8.1.1 Use Classification

Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9 Toxicity

9.1 Toxicological Information

9.1.1 Hepatotoxicity

In large early clinical trials, elevations in serum aminotransferase levels were common during dacomitinib therapy, arising in 40% of patients treated with standard doses. However, most elevations were transient and asymptomatic, and they rarely led to dose modification or discontinuation. Serum ALT elevations above 5 times the ULN occurred in only 1.4% of patients, these rates being lower than with other EGRF inhibitors such as erlotinib and gefitinib. Serum alkaline phosphatase elevations also occurred but were not common. There were no instances of clinically apparent liver injury with jaundice. However, clinical experience with dacomitinib has been limited.

Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

9.1.2 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the clinical use of dacomitinib during breastfeeding. Because dacomitinib is 98% bound to plasma proteins, the amount in milk is likely to be low. However, because of its potential toxicity in the breastfed infant and its half-life of 70 hours, the manufacturer recommends that breastfeeding be discontinued during dacomitinib therapy and for at least 17 days after the last dose.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

9.1.3 Protein Binding

Dacomitinib is known to present a protein binding of 98%.

10 Associated Disorders and Diseases

11 Literature

11.1 Consolidated References

11.2 NLM Curated PubMed Citations

11.3 Chemical Co-Occurrences in Literature

11.4 Chemical-Gene Co-Occurrences in Literature

11.5 Chemical-Disease Co-Occurrences in Literature

12 Patents

12.1 Depositor-Supplied Patent Identifiers

12.2 WIPO PATENTSCOPE

12.3 FDA Orange Book Patents

12.4 Chemical Co-Occurrences in Patents

12.5 Chemical-Disease Co-Occurrences in Patents

12.6 Chemical-Gene Co-Occurrences in Patents

13 Interactions and Pathways

13.1 Chemical-Target Interactions

13.2 Drug-Drug Interactions

13.3 Drug-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.

14 Biological Test Results

14.1 BioAssay Results

15 Classification

15.1 MeSH Tree

15.2 NCI Thesaurus Tree

15.3 KEGG: Drug

15.4 KEGG: USP

15.5 KEGG: ATC

15.6 KEGG: Target-based Classification of Drugs

15.7 KEGG: Drug Groups

15.8 KEGG: Drug Classes

15.9 ChemIDplus

15.10 ChEMBL Target Tree

15.11 EPA DSSTox Classification

15.12 MolGenie Organic Chemistry Ontology

16 Information Sources

  1. ChEMBL
    LICENSE
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    http://www.ebi.ac.uk/Information/termsofuse.html
  2. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  6. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  7. DailyMed
  8. LiverTox
  9. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  10. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  11. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  12. Drugs and Lactation Database (LactMed)
  13. Drugs@FDA
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  14. EU Clinical Trials Register
  15. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  16. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  17. Japan Pharmaceuticals and Medical Devices Agency (PMDA)
  18. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  19. Metabolomics Workbench
  20. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. NCI Cancer Drugs
  22. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  23. Pharos
    LICENSE
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    https://pharos.nih.gov/about
  24. Wikidata
    (2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide hydrate (1:1)
    https://www.wikidata.org/wiki/Q72451128
  25. Wikipedia
  26. PubChem
  27. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
  28. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  29. PATENTSCOPE (WIPO)
CONTENTS