NERATINIB MALEATE ANHYDROUS

Details

Stereochemistry	ACHIRAL
Molecular Formula	C30H29ClN6O3.C4H4O4
Molecular Weight	673.115
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	2
Charge	0

SHOW SMILES / InChI

Structure of NERATINIB MALEATE ANHYDROUS

SMILES

OC(=O)\C=C/C(O)=O.CCOC1=C(NC(=O)\C=C\CN(C)C)C=C2C(=C1)N=CC(C#N)=C2NC3=CC=C(OCC4=NC=CC=C4)C(Cl)=C3

InChI

InChIKey=VXZCUHNJXSIJIM-MEBGWEOYSA-N

InChI=1S/C30H29ClN6O3.C4H4O4/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;5-3(6)1-2-4(7)8/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38);1-2H,(H,5,6)(H,7,8)/b9-7+;2-1-

HIDE SMILES / InChI

Molecular Formula	C30H29ClN6O3
Molecular Weight	557.043
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Molecular Formula	C4H4O4
Molecular Weight	116.0722
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
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

Targets

Primary Target	Pharmacology	Condition	Potency
Receptor protein-tyrosine kinase erbB-2 35	Inhibitor 8,297		59.0 nM [IC50]
Epidermal growth factor receptor erbB1 58	Inhibitor 8,297		92.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
HER2-overexpressed/amplified breast cancer 3	Primary	Approved 8,429	NERLYNX
Breast cancer 434	Primary	Phase III 656	Unknown
Non-small cell lung cancer 206	Primary	Phase II 1,132	Unknown
Colorectal cancer 101	Primary	Phase II 1,132	Unknown

C_max

Value	Dose	Analyte	Population
73.1 ng/mL	240 mg 1 times / day steady-state, oral	NERATINIB blood	Homo sapiens
81.5 ng/mL	240 mg 1 times / day steady-state, oral	NERATINIB blood	Homo sapiens
76.3 ng/mL	240 mg single, oral	NERATINIB blood	Homo sapiens
71.8 ng/mL	240 mg single, oral	NERATINIB blood	Homo sapiens

AUC

Value	Dose	Analyte	Population
1060 ng × h/mL	240 mg 1 times / day steady-state, oral	NERATINIB blood	Homo sapiens
1110 ng × h/mL	240 mg 1 times / day steady-state, oral	NERATINIB blood	Homo sapiens
1640 ng × h/mL	240 mg single, oral	NERATINIB blood	Homo sapiens
891 ng × h/mL	240 mg single, oral	NERATINIB blood	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
14.6 h	240 mg 1 times / day steady-state, oral	NERATINIB blood	Homo sapiens
22.7 h	240 mg 1 times / day steady-state, oral	NERATINIB blood	Homo sapiens
14.3 h	240 mg single, oral	NERATINIB blood	Homo sapiens
12.6 h	240 mg single, oral	NERATINIB blood	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%			NERATINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
400 mg 1 times / day steady, oral Highest studied dose	unhealthy, 49.5 years (range: 42-63 years) n = 6	DLT: Diarrhea... Disc. AE: Fatigue...
240 mg 1 times / day steady, oral Recommended	unhealthy, 52 years n = 1408	DLT: Diarrhea, Diarrhea...
240 mg 1 times / day steady, oral Recommended	unhealthy, 52 years n = 1408	Disc. AE: Nausea, Abdominal pain... Other AEs: Nausea, Abdominal pain...
240 mg 1 times / day steady, oral Recommended	unhealthy, 52 years n = 1408	Other AEs: Bilirubin increased, Bilirubin increased...
180 mg 1 times / day steady, oral	unhealthy, 56.5 years (range: 46-90 years) n = 6	DLT: Diarrhea... Disc. AE: Fatigue...

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AEs

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AE	Significance	Dose	Population
Fatigue	all grades, 5 patients Disc. AE	400 mg 1 times / day steady, oral Highest studied dose	unhealthy, 49.5 years (range: 42-63 years) n = 6
Diarrhea	grade 3, 3 patients DLT, Disc. AE	400 mg 1 times / day steady, oral Highest studied dose	unhealthy, 49.5 years (range: 42-63 years) n = 6
Diarrhea	all grades, 95% DLT, Disc. AE	240 mg 1 times / day steady, oral Recommended	unhealthy, 52 years n = 1408
Diarrhea	grade 3, 40% DLT, Disc. AE	240 mg 1 times / day steady, oral Recommended	unhealthy, 52 years n = 1408
Diarrhea	grade 4, 0.1% DLT, Disc. AE	240 mg 1 times / day steady, oral Recommended	unhealthy, 52 years n = 1408

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767 inducer 389	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,461 CYP2C19 1,478 CYP1A2 1,524 CYP2B6 810 L-type Ca channels 9	FMO 35 CYP3A 191	CYP1A2 701 CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	no
CYP2B6 1,001	inducer 1,573	no
CYP2B6 1,001	inhibitor 3,277	no
CYP2C19 1,553	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
FMO 35	substrate 3,367	minor
CYP3A 191	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:61397	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:61397
ChemicalBook	CB2855051	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2855051
MolPort	MolPort-006-069-389	https://www.molport.com/shop/molecule-link/MolPort-006-069-389
Selleck Chemicals	Neratinib(HKI-272)	http://www.selleckchem.com/products/Neratinib(HKI-272).html
ZINC	ZINC000003916214	http://zinc15.docking.org/substances/ZINC000003916214

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PubMed

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Title	Date	PubMed
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378
A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development.	2013 Nov	23956101

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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
Record UNII	9RM7XY23ZS
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NERATINIB MALEATE ANHYDROUS

Common Name

English

NERATINIB MALEATE

Preferred Name

English

Neratinib maleate [WHO-DD]

Common Name

English

2-BUTENAMIDE, N-(4-((3-CHLORO-4-(2-PYRIDINYLMETHOXY)PHENYL)AMINO)-3-CYANO-7-ETHOXY-6-QUINOLINYL)-4-(DIMETHYLAMINO)-, (2E)-, (2Z)-2-BUTENEDIOATE (1:1)

Systematic Name

English

NERATINIB MALEATE [MI]

Common Name

English

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Classification Tree

Code System

Code

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

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Code System

Code

Type

Description

MERCK INDEX

m7827

PRIMARY

Merck Index

EVMPD

SUB194473

PRIMARY

DAILYMED

9RM7XY23ZS

PRIMARY

EPA CompTox

DTXSID801027861

PRIMARY

CAS

915942-22-2

PRIMARY

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Related Record

Type

Details


					KF5ZU8T8W2

NERATINIB MALEATE MONOHYDRATE

SOLVATE->ANHYDROUS


					JJH94R3PWB

NERATINIB

PARENT -> SALT/SOLVATE

Amount:

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Related Record

Type

Details


					JJH94R3PWB

NERATINIB

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
SOLUBILITY	CHEMICAL	32.9 mg/mL (average) Sparingly Soluble	FINAL pH CHEMICAL 1.2 (average) SOLVENT CHEMICAL pH 1.2 POTASSIUM CHLROIDE TEMPERATURE PHYSICAL 37 °C (average)
SOLUBILITY	CHEMICAL	2.01 mg/mL (average) SLIGHTLY SOLUBLE	SOLVENT CHEMICAL pH 3.1 POTASSIUM PHTHALATE BUFFER FINAL pH CHEMICAL 3.1 (average) TEMPERATURE PHYSICAL 37 °C (average)
SOLUBILITY	CHEMICAL	INSOLUBLE	TEMPERATURE PHYSICAL 37 °C (average) SOLVENT CHEMICAL pH 5.0 POTASSIUM PHTHLATE BUFFER

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator