Identification

Name
Neratinib
Accession Number
DB11828
Type
Small Molecule
Groups
Approved, Investigational
Description

Neratinib was approved in July 2017 for use as an extended adjuvant therapy in Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer. Approval was granted to Puma Biotechnology Inc. for the tradename Nerlynx. Neratinib is currently under investigation for use in many other forms of cancer.

Structure
Thumb
Synonyms
Not Available
External IDs
HKI-272
Product Ingredients
IngredientUNIICASInChI Key
Neratinib Maleate9RM7XY23ZS915942-22-2VXZCUHNJXSIJIM-MEBGWEOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NerlynxTablet40 mg/1OralPuma Biotechnology, Inc.2017-07-17Not applicableUs
Categories
UNII
JJH94R3PWB
CAS number
698387-09-6
Weight
Average: 557.05
Monoisotopic: 556.1989665
Chemical Formula
C30H29ClN6O3
InChI Key
JWNPDZNEKVCWMY-VQHVLOKHSA-N
InChI
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+
IUPAC Name
(2E)-N-[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
SMILES
CCOC1=C(NC(=O)\C=C\CN(C)C)C=C2C(NC3=CC=C(OCC4=CC=CC=N4)C(Cl)=C3)=C(C=NC2=C1)C#N

Pharmacology

Indication

For use as an extended adjuvant treatment in adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy [Label].

Associated Conditions
Pharmacodynamics

Neratinib is a tyrosine kinase inhibitor which exhibits antitumor action against Epidermal Growth Factor Receptor (EGFR), HER2, and Human Epidermal Growth Factor Receptor 4 (HER4) postive carcinomas [Label].

Mechanism of action

Neratinib binds to and irreversibly inhibits EGFR, HER2, and HER4 [Label]. This prevents auotphoshorylation of tyrosine residues on the receptor and reduces oncogenic signalling through the mitogen-activated protein kinase and Akt pathways.

TargetActionsOrganism
AEpidermal growth factor receptor
inhibitor
Human
Absorption

Neratinib and its major active metabolites M3. M6, and M7 have a Tmax of 2-8 h [Label]. Administration with a high fat meal increases Cmax by 1.7-fold and total exposure by 2.2-fold. Administration with a standard meal increases Cmax by 1.2-fold and total exposure by 1.1-fold. Administration with gastric acid reducing agents such as proton pump inhibitors reduces Cmax by 71% and total exposure by 65%.

Volume of distribution

The apparent volume of distribution at steady state is 6433 L [Label].

Protein binding

Neratinib is over 99% bound to human plasma proteins [Label]. It binds both human serum albumin and α1 acid glycoprotein.

Metabolism

Neratinib is mainly undergoes metabolism via CYP3A4 [Label]. It is also metabolized by flavin-containing monooxygenase to a lesser extent. The systemic exposures of neratinib's active metabolites M3, M6, M7, and M11 are 15%, 33%, 22%, and 4%.

Route of elimination

97.1% of the total dose is excreted in the feces and 1.13% in the urine [Label].

Half life

The mean half life of elimination ranges from 7-17 h following a single dose [Label]. The mean plasma half life during multiple doses is 14.6 h for neratinib, 21.6 h for M3, 13.8 h for M6, and 10.4 h for M7.

Clearance

The total clearance during multiple doses is 216 L/h for after the first dose and 281 L/h during steady state [Label].

Toxicity

Use of neratinib may produce diarrhea and hepatotoxicity as clinically significant adverse effects [Label]. Serious adverse reactions in the neratinib arm of the clinical trials included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), alanine aminotransferase increase (0.3%), aspartate aminotransferase increase (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Neratinib can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Neratinib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Neratinib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Neratinib.
5-androstenedioneThe metabolism of Neratinib can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Neratinib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Neratinib.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Neratinib.
AbirateroneThe metabolism of Neratinib can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Neratinib can be decreased when combined with Acalabrutinib.
Food Interactions
Not Available

References

General References
Not Available
External Links
PubChem Compound
9915743
PubChem Substance
347828174
ChemSpider
8091392
BindingDB
50161957
ChEMBL
CHEMBL180022
Wikipedia
Neratinib
FDA label
Download (658 KB)
MSDS
Download (24 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers3
1CompletedNot AvailableHepatic Insufficiency1
1CompletedTreatmentAdvanced Malignant Solid Tumors3
1CompletedTreatmentCancer, Breast2
1CompletedTreatmentHealthy Volunteers7
1CompletedTreatmentMalignant Carcinoma / Neoplasms1
1CompletedTreatmentNeoplasms, Breast1
1CompletedTreatmentTumors1
1RecruitingTreatmentMalignant Neoplasm of Breast / Malignant Neoplasms of Digestive Organs / Malignant Neoplasms of Female Genital Organs / Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites / Malignant Neoplasms of Independent (Primary) Multiple Sites / Malignant Neoplasms of Lip Oral Cavity and Pharynx / Malignant Neoplasms of Mesothelial and Soft Tissue / Malignant Neoplasms of Respiratory and Intrathoracic Organs / Malignant Neoplasms of Thyroid and Other Endocrine Glands / Malignant Neoplasms of Urinary Tract / Neoplasms of Uncertain or Unknown Behavior1
1TerminatedTreatmentTumors, Solid1
1WithdrawnTreatmentHealthy Volunteers1
1, 2Active Not RecruitingTreatmentColorectal Cancers1
1, 2CompletedTreatmentAdvanced Breast Cancer1
1, 2CompletedTreatmentAdvanced Breast Cancer / Advanced Malignant Solid Tumors / Neoplasms, Breast1
1, 2CompletedTreatmentAdvanced Malignant Solid Tumors / Cancer, Breast1
1, 2CompletedTreatmentCancer, Breast2
1, 2RecruitingTreatmentCancer, Breast2
1, 2RecruitingTreatmentLeukemias / Malignant Lymphomas / Tumors, Central Nervous System / Tumors, Solid1
1, 2RecruitingTreatmentMalignant Neoplasm of Breast1
2Active Not RecruitingTreatmentCancer, Breast1
2CompletedTreatmentAdvanced Breast Cancer / Cancer, Breast2
2CompletedTreatmentCancer, Breast1
2CompletedTreatmentHER2-mutant Non-Small Cell Lung Cancer1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Neoplasms, Lung1
2CompletedTreatmentNeoplasms / Neoplasms, Breast1
2RecruitingOtherAdvanced Breast Cancer1
2RecruitingTreatmentCancer, Breast1
2RecruitingTreatmentCancer, Breast / Neoplasms, Breast / Tumors, Breast1
2RecruitingTreatmentEarly Stage HER2+ Breast Cancer1
2RecruitingTreatmentFibrolamellar Carcinoma / Malignant Solid Tumours / Tumors, Solid1
2RecruitingTreatmentGlioblastomas1
2RecruitingTreatmentHER2 Positive Breast Carcinoma / Recurrent Breast Carcinoma / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
2RecruitingTreatmentHer2-Positive Breast Cancer1
2RecruitingTreatmentMetastatic Colorectal Cancers1
2RecruitingTreatmentNeoplasms, Breast1
3Active Not RecruitingTreatmentCancer, Breast1
3Active Not RecruitingTreatmentHER2+ Metastatic Breast Cancer (MBC)1
Not AvailableNo Longer AvailableNot AvailableBladder Cancers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral40 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8790708No2010-11-052030-11-05Us
US9139558No2008-10-152028-10-15Us
US6288082No1999-09-242019-09-24Us
US9211291No2010-03-242030-03-24Us
US7982043No2005-10-082025-10-08Us
US9630946No2008-10-152028-10-15Us
US8518446No2010-11-202030-11-20Us
US7399865No2005-12-292025-12-29Us
US10035788No2008-10-152028-10-15Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00674 mg/mLALOGPS
logP4.72ALOGPS
logP4.47ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)12.55ChemAxon
pKa (Strongest Basic)8.81ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area112.4 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity157.29 m3·mol-1ChemAxon
Polarizability58.1 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as 4-aminoquinolines. These are organic compounds containing an amino group attached to the 4-position of a quinoline ring system.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Aminoquinolines and derivatives
Direct Parent
4-aminoquinolines
Alternative Parents
Aminophenyl ethers / Phenoxy compounds / N-arylamides / Aniline and substituted anilines / Alkyl aryl ethers / Aminopyridines and derivatives / Chlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Trialkylamines
show 10 more
Substituents
4-aminoquinoline / Aminophenyl ether / Phenoxy compound / Aniline or substituted anilines / N-arylamide / Phenol ether / Alkyl aryl ether / Aminopyridine / Chlorobenzene / Halobenzene
show 29 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Inhibits the tyrosine kinase activity of the receptor to prevent autophosphorylation.
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Trimethylamine monooxygenase activity
Specific Function
Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an impor...
Gene Name
FMO3
Uniprot ID
P31513
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 3
Molecular Weight
60032.975 Da

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on October 20, 2016 14:51 / Updated on November 02, 2018 09:02