General
Preferred name
DACOMITINIB
Synonyms
PF-00299804 (hydrate) ()
PF-299804 (hydrate) ()
DACOMITINIB HYDRATE ()
PF-00299804, PF-00299804-03 ()
PF-299804 ()
PF-00299804 ()
PF299 ()
PF00299804 ()
PF 00299804 ()
PF299804 ()
PF 299804 ()
DACOMITINIB ANHYDROUS ()
S2727 ()
Dacomitinib (hydrate) ()
Dacomitinib (PF-00299804) ()
PF299804,PF299 ()
Dacomitinib monohydrate ()
PF-00299804-03 ()
Vizimpro ()
Dacomitinib hydrate ()
P&D ID
PD010693
CAS
1110813-31-4
1042385-75-0
Tags
available
covalent binder
drug
Approved by
FDA
PMDA
EMA
First approval
2018
Drug indication
Non-small-cell lung cancer
Drug Status
approved
investigational
Max Phase
4.0
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
DESCRIPTION
Dacomitinib is a second-generation, irreversible pan inhibitor of HER tyrosine kinases (EGFR, and ERBBs) that is being developed by Pfizer.
Results from the ARCHER 1050 Phase 3 randomised, open-label trial (NCT01774721) that directly compared dacomitinib against , as first-line treatment for patients with EGFR-mutation +ve non-small-cell lung cancer (NSCLC), reported that dacomitinib significantly increased progression-free survival and overall survival compared to gefitinib . However, dacomitinib's use may be limited in NSCLC patients with brain metastases, as these patients we excluded from the trial because dacomitinib's ability to cross the blood-brain-barrier has not been fully confirmed. This is unlike (a third-generation irreversible EGFR inhibitor) which has confirmed brain penetrance, and which does not appear to cause the same dose-limiting toxicities that afflict dacomitinib. Pfizer posted a press release in April 2018 which reported that both the FDA and EMA had accepted regulatory submissions (New Drug Application and Marketing Authorization Application respectively) for review of dacomitinib as a therapy for metastatic NSCLC with EGFR-activating mutations. The FDA granted Priority Review status for the submitted NDA.
Results from the ARCHER 1050 Phase 3 randomised, open-label trial (NCT01774721) that directly compared dacomitinib against , as first-line treatment for patients with EGFR-mutation +ve non-small-cell lung cancer (NSCLC), reported that dacomitinib significantly increased progression-free survival and overall survival compared to gefitinib . However, dacomitinib's use may be limited in NSCLC patients with brain metastases, as these patients we excluded from the trial because dacomitinib's ability to cross the blood-brain-barrier has not been fully confirmed. This is unlike (a third-generation irreversible EGFR inhibitor) which has confirmed brain penetrance, and which does not appear to cause the same dose-limiting toxicities that afflict dacomitinib. Pfizer posted a press release in April 2018 which reported that both the FDA and EMA had accepted regulatory submissions (New Drug Application and Marketing Authorization Application respectively) for review of dacomitinib as a therapy for metastatic NSCLC with EGFR-activating mutations. The FDA granted Priority Review status for the submitted NDA.
MOA
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.[A40011] The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L.[A40009]; ; 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.[A39624] 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.[A40016]
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.[FDA 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.[A40012]
METABOLISM
Dacomitinib presents an oxidative and conjugative metabolism marked mainly by the activity of glutathione and cytochrome P450 enzymes.[A40012] After metabolism, its major circulating metabolite is an O-desmethyl dacomitinib form named PF-05199265.[A40014] 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.[A40019]; ; From these metabolic studies, it was shown that dacomitinib inhibited strongly the activities of CYP2D6.[A40013]
DESCRIPTION
Dacomitinib is a second-generation, irreversible pan inhibitor of HER tyrosine kinases (EGFR, and ERBBs) that was developed by Pfizer.
Results from the ARCHER 1050 Phase 3 randomised, open-label trial (NCT01774721) that directly compared dacomitinib against , as first-line treatment for patients with EGFR-mutation +ve non-small-cell lung cancer (NSCLC), reported that dacomitinib significantly increased progression-free survival and overall survival compared to gefitinib . Dacomitinib's use may be limited in NSCLC patients with brain metastases, as these patients were excluded from the trial because dacomitinib's ability to cross the blood-brain-barrier has not been fully confirmed. This is unlike (another third-generation irreversible EGFR inhibitor) which has confirmed brain penetrance, and which does not appear to cause the same dose-limiting toxicities that afflict dacomitinib. In April 2018 both the FDA and EMA accepted regulatory submissions (New Drug Application and Marketing Authorization Application respectively) for review of dacomitinib as a therapy for metastatic NSCLC with EGFR-activating mutations. The FDA granted Priority Review status for the submitted NDA.
SARS-CoV-2: A high-throughput screen identified potential anti-SARS-CoV-2 activity in cell infection assays . (GtoPdb)
Results from the ARCHER 1050 Phase 3 randomised, open-label trial (NCT01774721) that directly compared dacomitinib against , as first-line treatment for patients with EGFR-mutation +ve non-small-cell lung cancer (NSCLC), reported that dacomitinib significantly increased progression-free survival and overall survival compared to gefitinib . Dacomitinib's use may be limited in NSCLC patients with brain metastases, as these patients were excluded from the trial because dacomitinib's ability to cross the blood-brain-barrier has not been fully confirmed. This is unlike (another third-generation irreversible EGFR inhibitor) which has confirmed brain penetrance, and which does not appear to cause the same dose-limiting toxicities that afflict dacomitinib. In April 2018 both the FDA and EMA accepted regulatory submissions (New Drug Application and Marketing Authorization Application respectively) for review of dacomitinib as a therapy for metastatic NSCLC with EGFR-activating mutations. The FDA granted Priority Review status for the submitted NDA.
SARS-CoV-2: A high-throughput screen identified potential anti-SARS-CoV-2 activity in cell infection assays . (GtoPdb)
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.[A40010]; ; 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.[A40009]; ; 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.[A40015]
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.[L4812]; ; 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.[A40018, A19201]
DESCRIPTION
On october 27, 2018, the FDA approved dacomitinib to treat metastatic non-small-cell lung cancer
(PKIDB)
DESCRIPTION
Potent and selective hepatitis B virus inhibitor
(Tocris Bioactive Compound Library)
DESCRIPTION
Dacomitinib is a second-generation small molecule inhibitor of the pan-epidermal growth factor receptor (EGFR) tyrosine kinase family (ErbB family) with potential anti-tumor activity.
(BOC Sciences Bioactive Compounds)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
5
Organisms
0
Compound Sets
30
AdooQ Bioactive Compound Library
Axon Medchem Screening Library
BOC Sciences Bioactive Compounds
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
Clinical kinase drugs
CovalentInDB
CZ-OPENSCREEN Bioactive Library
Drug Repurposing Hub
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
EU-OPENSCREEN Bioactive Compound Library
EUbOPEN Chemogenomics Library
Guide to Pharmacology
LSP-MoA library (Laboratory of Systems Pharmacology)
LSP-OptimalKinase library (Laboratory of Systems Pharmacology)
NCATS Inxight Approved Drugs
NIH Approved Oncology Drugs
PKIDB
ReFrame library
Selleckchem Bioactive Compound Library
Tocris Bioactive Compound Library
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
41
Molecular Weight
469.17
Hydrogen Bond Acceptors
6
Hydrogen Bond Donors
2
Rotatable Bonds
7
Ring Count
4
Aromatic Ring Count
3
cLogP
5.16
TPSA
79.38
Fraction CSP3
0.29
Chiral centers
0.0
Largest ring
6.0
QED
0.47
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Targets
EGFR
Pathway
Angiogenesis
JAK/STAT Signaling
Tyrosine Kinase/Adaptors
Protein Tyrosine Kinase/RTK
Apoptosis
Target
HER2/ErbB2
EGFR, ERBB2, ERBB4
HER inhibitor
Apoptosis related,EGFR,HER2
MOA
Inhibitor
EGFR inhibitor
Solubility
Soluble in DMSO
Recommended Cell Concentration
None
Source data
