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Details

Stereochemistry ACHIRAL
Molecular Formula C30H29ClN6O3
Molecular Weight 557.043
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of NERATINIB

SMILES

CCOC1=CC2=C(C=C1NC(=O)\C=C\CN(C)C)C(NC3=CC(Cl)=C(OCC4=CC=CC=N4)C=C3)=C(C=N2)C#N

InChI

InChIKey=JWNPDZNEKVCWMY-VQHVLOKHSA-N
InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+

HIDE SMILES / InChI

Molecular Formula C30H29ClN6O3
Molecular Weight 557.043
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Description

Neratinib (HKI-272) is a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib is a modified form of the discontinued compound pelitinib, and was originally being develoAdditionally, phase II development of oral neratinib as a neoadjuvant therapy for breast cancer, as a second-line therapy for non-small cell lung cancer, and for other solid tumours is also in progress in numerous countries worldwide. ped by Wyeth (later Pfizer). Oral neratinib is awaiting approval as an extended adjuvant therapy for breast cancer in the EU and in the US. Blocking HER2 function by a small molecule kinase inhibitor, such as neratinib, represents an attractive alternate strategy for the growth inhibition of HER2-positive tumours.

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase.
2004 Jun 1
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
Irreversible EGFR inhibitor EKB-569 targets low-LET γ-radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma.
2011
Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors.
2011 Mar 10
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development.
2013 Nov
Patents

Sample Use Guides

In Vivo Use Guide
Patients who received 40, 80, or 120 mg experienced no dose-limiting toxicities. The study determined the maximum tolerated dose at 320 mg, with 240 mg being the therapeutic dose.
Route of Administration: Oral
In Vitro Use Guide
both very low (10 nM) and physiologically attainable concentrations of neratinib (133 nM) significantly inhibited the autophosphorylation of HER2/neu and activation of S6 in primary carcinosarcoma cells
Substance Class Chemical
Created
by admin
on Tue Mar 06 11:10:26 UTC 2018
Edited
by admin
on Tue Mar 06 11:10:26 UTC 2018
Record UNII
JJH94R3PWB
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NERATINIB
INN   MART.   MI   USAN   WHO-DD  
INN   USAN  
Official Name English
2-BUTENAMIDE, N-(4-((3-CHLORO-4-(2-PYRIDINYLMETHOXY)PHENYL)AMINO)-3-CYANO-7-ETHOXY-6-QUINOLINYL)-4-(DIMETHYLAMINO)-, (2E)-
Systematic Name English
HKI-272
Code English
CDP-820
Code English
NERATINIB [WHO-DD]
Common Name English
NERATINIB [MART.]
Common Name English
NERATINIB [MI]
Common Name English
NERATINIB [USAN]
Common Name English
NERATINIB [INN]
Common Name English
(2E)-N-(4-((3-CHLORO-4-((PYRIDIN-2-YL)METHOXY)PHENYL)AMINO)-3-CYANO-7-ETHOXYQUINOLIN-6-YL)-4-(DIMETHYLAMINO)BUT-2-ENAMIDE
Systematic Name English
Code System Code Type Description
WIKIPEDIA
NERATINIB
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
ChEMBL
CHEMBL180022
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
PUBCHEM
9915743
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY SWITZERF
EVMPD
SUB32232
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
EPA CompTox
698387-09-6
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
INN
8878
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
RXCUI
1940643
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
CAS
698387-09-6
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
NCI_THESAURUS
C49094
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY
MERCK INDEX
M7827
Created by admin on Tue Mar 06 11:10:26 UTC 2018 , Edited by admin on Tue Mar 06 11:10:26 UTC 2018
PRIMARY Merck Index
Related Record Type Details
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
METABOLIC ENZYME -> SUBSTRATE
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
BINDER -> LIGAND
ex vivo protein binding of neratinib in human plasma samples from clinical study in healthy subjects as determined using ult racentrifugation was 88%
BINDING
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
Percent inhibition of specific binding
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
TARGET -> INHIBITOR
Cyclin D1 expression in BT474 cells
INHIBITOR
IC50
CELL -> INHIBITOR
CELL PROLIFERATION
IC50
TARGET -> INHIBITOR
HER2 ligand-independent receptor phosphorylation in BT474
IRREVERSIBLE INHIBITOR
IC50
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
TARGET -> INHIBITOR
EGFR-dependent receptor phosphorylation in A431 cells
IC50
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
METABOLIC ENZYME -> NON-INDUCER
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
METABOLIC ENZYME -> NON-INHIBITOR
IC50
TARGET -> INHIBITOR
IC50
TARGET -> INHIBITOR
IC50
BINDER -> LIGAND
In vitro, neratinib was highly bound (N 99 %) to human plasma proteins at cl inica l exposures. click to edit
BINDING
TARGET -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
TRANSPORTER -> INHIBITOR
Neratinib concentration at 10 microM
INHIBITOR
Percent inhibition of specific binding
TARGET -> INHIBITOR
Radioligand binding assay
BINDING
IC50
Related Record Type Details
METABOLITE LESS ACTIVE -> PARENT
METABOLITE ACTIVE -> PARENT
Inhibition of HER2 kinase activity (Neratinib IC50 = 17 nM)
INHIBITOR
IC50
METABOLITE LESS ACTIVE -> PARENT
IC50 for HER2 kinase activity was up to 19 fold higher when compared to neratinib.
INHIBITOR
IC50
Related Record Type Details
ACTIVE MOIETY