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Details

Stereochemistry ACHIRAL
Molecular Formula C24H25ClFN5O2
Molecular Weight 469.939
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of DACOMITINIB ANHYDROUS

SMILES

COC1=CC2=C(C=C1NC(=O)\C=C\CN3CCCCC3)C(NC4=CC(Cl)=C(F)C=C4)=NC=N2

InChI

InChIKey=LVXJQMNHJWSHET-AATRIKPKSA-N
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+

HIDE SMILES / InChI

Molecular Formula C24H25ClFN5O2
Molecular Weight 469.939
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Description

Dacomitinib is an oral, once-daily, pan-HER inhibitor. It is an irreversible inhibitor of HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases. Dacomtinib is being evaluated in phase 3 clinical trials against nonsmall-cell lung cancer. Direct comparison with erlotinib did not show superiority of dacomtinib, but subgroup analysis have demonstrated that subgroup with exon 19 deletion had favorable outcomes with dacomitinib. In addition to nonsmall-cell lung cancer dacomtinib is being evaluated against esophagus, head and neck and other neoplasms. Due to its ability to pass through blood-brain barrier, dacomitinib can be used to treat brain tumors.

CNS Activity

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
Irreversible protein kinase inhibitors: balancing the benefits and risks.
2012 Jul 26
Patents

Sample Use Guides

In Vivo Use Guide
In phase III study against non small cell lung cancer dacomitinib was administered orally at a dose 45 mg a day.
Route of Administration: Oral
In Vitro Use Guide
Cells were seeded in duplicate at 5 × 103 to 5 × 104 cells per well in 24-well plates. A day after plating, dacomitinib was added at 10 μmol/L and 2-fold dilutions over 12 concentrations were carried out to generate a dose–response curve. Control wells without the drug were also seeded. The cells were counted on day 1 when the drug was added, as well as after 6 days when the experiment ended. After the trypsinization cells were placed in an Isotone solution and immediately counted using a Coulter Z1 particle counter (Beckman Coulter, Inc.). The suspension cultures were counted using a Coulter Vi-Cell counter (Beckman Coulter, Inc.). As a group, HER2-amplified cell lines were most sensitive to growth inhibition by dacomitinib (IC50 < 1 μmol/L in 14 of 16 lines).
Substance Class Chemical
Created
by admin
on Mon Oct 21 22:22:53 UTC 2019
Edited
by admin
on Mon Oct 21 22:22:53 UTC 2019
Record UNII
2XJX250C20
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
DACOMITINIB ANHYDROUS
Common Name English
(2E)-N-(4-((3-CHLORO-4-FLUOROPHENYL)AMINO)-7-METHOXYQUINAZOLIN-6-YL)-4-PIPERIDIN-1-YLBUT-2-ENAMIDE
Systematic Name English
DACOMITINIB [WHO-DD]
Common Name English
PF-00299804
Code English
DACOMITINIB [INN]
Common Name English
Code System Code Type Description
INN
9314
Created by admin on Mon Oct 21 22:22:53 UTC 2019 , Edited by admin on Mon Oct 21 22:22:53 UTC 2019
PRIMARY
CAS
1110813-31-4
Created by admin on Mon Oct 21 22:22:53 UTC 2019 , Edited by admin on Mon Oct 21 22:22:53 UTC 2019
PRIMARY
PUBCHEM
11511120
Created by admin on Mon Oct 21 22:22:53 UTC 2019 , Edited by admin on Mon Oct 21 22:22:53 UTC 2019
PRIMARY
EPA CompTox
1110813-31-4
Created by admin on Mon Oct 21 22:22:53 UTC 2019 , Edited by admin on Mon Oct 21 22:22:53 UTC 2019
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
The reversal effect on ABCB1-overexpressing cells is more potent than that on ABCG2-overexpressing cells. Dacomitinib at 1.0€?M significantly reversed drug resistance mediated by ABCB1 and ABCG2, but not ABCC1, doing so by antagonizing the drug efflux function in ABCB1- and ABCG2-overexpressing cell lines.
BINDING
MAY BE CLINICALLY SIGNIFICANT
TRANSPORTER -> INHIBITOR
The reversal effect on ABCB1-overexpressing cells is more potent than that on ABCG2-overexpressing cells. Dacomitinib at 1.0€?M significantly reversed drug resistance mediated by ABCB1 and ABCG2, but not ABCC1, doing so by antagonizing the drug efflux function in ABCB1- and ABCG2-overexpressing cell lines.
BINDING
MAY BE CLINICALLY SIGNIFICANT
TARGET -> INHIBITOR
IRREVERSIBLE INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
IN-VITRO
METABOLIC ENZYME -> SUBSTRATE
IN-VITRO
SALT/SOLVATE -> PARENT
Related Record Type Details
METABOLITE -> PARENT
MINOR
FECAL
METABOLITE -> PARENT
In addition, it is likely that dacomitinib underwent glutathione conjugation with subsequent hydrolysis to form the cysteine conjugate (M2).
MAJOR
FECAL
METABOLITE -> PARENT
MINOR
FECAL
METABOLITE ACTIVE -> PARENT
Concentrations of PF-05199265 peaked at 6 h post-dose.
MAJOR
PLASMA
METABOLITE ACTIVE -> PARENT
MAJOR
FECAL; PLASMA
METABOLITE ACTIVE -> PARENT
Fecal homogenate extracts indicated that metabolism of [14C] dacomitinib was similar and extensive in all the 6 subjects. The four most abundant drugrelated components were dacomitinib (20 %), PF-05199265 (20 %), a cysteine conjugate (M2; 9.5 %), and a monooxygenated metabolite (M7; 5.1 %)
MAJOR
FECAL
Related Record Type Details
ACTIVE MOIETY