Dacomitinib

CovInDB Drug

DB11963

Name

Dacomitinib

Molecular Formula

C₂₄H₂₅ClFN₅O₂

Molecular Weight

469.17 g/mol

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.Some evidence in the literature suggests the therapeutic potential of dacomitinib in the epithelial ovarian cancer model, although further investigations are needed.

Status

approved, investigational

Structure

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SDF 2D SDF 3D

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.

Mechanism of action

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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.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.

IUPAC Name

(E)-N-[4-(3-chloro-4-fluoro-anilino)-7-methoxy-quinazolin-6-yl]-4-(1-piperidyl)but-2-enamide

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+

InChI Key

LVXJQMNHJWSHET-AATRIKPKSA-N

Canonical SMILES

COC1=C(NC(=O)\C=C\CN2CCCCC2)C=C2C(NC3=CC(Cl)=C(F)C=C3)=NC=NC2=C1

Reference

DrugBank

Warhead

Micheal Acceptor

Target

Epidermal growth factor receptor   [ UniProt: P00533 ]

Site

CYS-797

Inhibition Mechanism

Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition

logP

4.88

Computed by ALOGPS

logS

-4.73

Computed by ALOGPS

Heavy Atom Count

33

Computed by RDKit

Ring Count

4

Computed by RDKit

Hydrogen Bond Acceptor Count

6

Computed by RDKit

Hydrogen Bond Donor Count

2

Computed by RDKit

Rotatable Bond Count

7

Computed by RDKit

Topological Polar Surface Area

79.38 Ų

Computed by RDKit

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No similar natural compounds found for this drug.