ERLOTINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H23N3O4
Molecular Weight	393.4357
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COCCOC1=CC2=NC=NC(NC3=CC=CC(=C3)C#C)=C2C=C1OCCOC

InChI

InChIKey=AAKJLRGGTJKAMG-UHFFFAOYSA-N

InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00530
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf

Erlotinib hydrochloride (trade name Tarceva, Genentech/OSIP, originally coded as OSI-774) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders. The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Epidermal growth factor receptor erbB1 62 Target ID: CHEMBL203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25882519	Antagonist 2849	1.2 nM [IC50]
Pregnane X receptor 36 Target ID: CHEMBL3401 Sources: http://www.drugbank.ca/drugs/DB00530	Agonist 2752
ATP-binding cassette sub-family G member 2 16 Target ID: CHEMBL5393 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27418107	Inhibitor 8504	2.23 µM [IC50]
PANC-1 5 Target ID: CHEMBL614139 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27010345	Inhibitor 8504	0.02 µM [IC50]
Serine/threonine-protein kinase B-raf 21 Target ID: CHEMBL5145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27010345	Inhibitor 8504	0.08 µM [IC50]
Epidermal growth factor receptor 49 Target ID: CHEMBL2363049 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27010345	Antagonist 2849	0.05 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Locally advanced or metastatic non-small cell lung cancer 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf	Primary		Approved 8583	TARCEVA Approved Use TARCEVA is a kinase inhibitor indicated for: Maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. Launch Date 2004
Locally advanced, unresectable or metastatic pancreatic cancer 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf	Primary		Approved 8583	TARCEVA Approved Use TARCEVA is a kinase inhibitor indicated for: Maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. Launch Date 2004

C_max

Value	Dose	Analyte	Population
1969.5 ng/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01032070	85 mg/m^2 1 times / day steady, oral dose: 85 mg/m^2 route of administration: oral experiment type: steady co-administered:	ERLOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: UNKNOWN food status: UNKNOWN
4.07 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19956953	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:	ERLOTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.25 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19956953	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	ERLOTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1108.89 ng/mL EXPERIMENT http://doi.org/10.4172/jbb.1000190	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:	ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.09 μg/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

AUC

Value	Dose	Analyte	Population
26716.7 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01032070	85 mg/m^2 1 times / day steady, oral dose: 85 mg/m^2 route of administration: oral experiment type: steady co-administered:	ERLOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: UNKNOWN food status: UNKNOWN
32 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19956953	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:	ERLOTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
29.9 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19956953	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	ERLOTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
25489.41 ng × h/mL EXPERIMENT http://doi.org/10.4172/jbb.1000190	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:	ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
15.2 μg × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

T_1/2

Value	Dose	Analyte	Population
12.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19956953	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:	ERLOTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
14.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/19956953	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	ERLOTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
36.2 h OTHER https://www.medicine.com/drug/erlotinib/hcp	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:	ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
14.33 h EXPERIMENT http://doi.org/10.4172/jbb.1000190	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:	ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
14.75 h OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
7% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf			ERLOTINIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
7% OTHER https://www.medicine.com/drug/erlotinib/hcp	150 mg single, oral dose: 150 mg route of administration: Oral experiment type: SINGLE co-administered:		ERLOTINIB HYDROCHLORIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252	inhibitor 2438 substrate 1193	substrate 1388 inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 1057 UGT1A1 246 UGT1A9 148 CYP1A1 132 CYP1A2 2153	CYP1A2 1197 CYP2C8 810 CYP1A1 389 CYP1B1 104 CYP2C19 1119 CYP3A4/5 91

Drug as perpetrator

Target	Modality	Activity
UGT1A1 303	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=51 Page: -	yes [IC50 0.93 uM]
UGT1A9 155	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=51 Page: -	yes [IC50 31 uM]
CYP1A1 272	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=48 Page: -	yes [IC50 <0.1 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -	yes [Ki 10 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -	yes [Ki 14.7 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=49 Page: -	yes [Ki 20 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=49 Page: -	yes [Ki 35.7 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -	yes [Ki 44 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -	major [Km 5.9 uM]	yes (co-administration study) Comment: Coadministration of erlotinib with ketoconazole, a potent inhibitor of CYP3A4, resulted in a significant (67%) increase in erlotinib exposure (Study NP16612). The CYP3A4 inducer rifampicin has been demonstrated to impact the exposure to erlotinib; in Study NP16638 co-administration led to a 64% reduction in erlotinib AUC. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -	minor
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=39 Page: -	no
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=39 Page: -	no
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=39 Page: -	no
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=47 Page: -	yes [Km 24 uM]
CYP1A1 389	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -	yes
CYP1B1 104	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=10 Page: -	yes
CYP3A4/5 91	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=47 Page: -	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva_biopharmr.PDF#page=11 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:114785	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:114785
ChemicalBook	CB9285914	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9285914
eMolecules	901844	https://www.emolecules.com/cgi-bin/more?vid=901844
MolPort	MolPort-003-847-084	https://www.molport.com/shop/molecule-link/MolPort-003-847-084
ZINC	ZINC000001546066	http://zinc15.docking.org/substances/ZINC000001546066

PubMed

Title	Date	PubMed
[New therapeutic targets and strategies in lung cancer].	2002 Aug	12199921
Gateways to clinical trials.	2002 Dec	12616965
Epithelial growth factor receptor interacting agents.	2002 Oct	12512382
Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors.	2003	14657536
Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.	2003	12848590
The future of cytotoxic therapy: selective cytotoxicity based on biology is the key.	2003	12793897
3D-QSAR and docking studies on 4-anilinoquinazoline and 4-anilinoquinoline epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.	2003 Aug	14703120
Erlotinib: a new therapeutic approach for non-small cell lung cancer.	2003 Aug	12882624
Clinical studies with non-iressa EGFR tyrosine kinase inhibitors.	2003 Aug	12867061
Specific method for determination of OSI-774 and its metabolite OSI-420 in human plasma by using liquid chromatography-tandem mass spectrometry.	2003 Aug 15	12906916
Targeting the epidermal growth factor receptor in non-small cell lung cancer.	2003 Dec 1	14676101
For investigational targeted drugs, combination trials pose challenges.	2003 Dec 3	14652234
Phase I studies of ZD1839 in patients with common solid tumors.	2003 Feb	12644981
Epidermal growth factor receptor as a therapeutic target in colorectal cancer.	2003 Feb	12620146
[Molecular-targeted therapy].	2003 Feb	12610866
[Molecular targetting therapy for non-small-cell lung neoplasms with EGF-R inhibitors].	2003 Feb 10	12652739
Clinical Trials in Cancer-SMi Conference. 11-12 June 2003, London, UK.	2003 Jul	12906014
Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients.	2003 Jul	12855621
Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer.	2003 Jul	12850190
Research retreat: Pfizer eliminates Sugen, shrinks cancer infrastructure.	2003 Jul 16	12865446
Epidermal growth factor receptor inhibitors: an update on their development as cancer therapeutics.	2003 Jun	12901223
Challenges and opportunities for Erlotinib (Tarceva): what does the future hold?	2003 Jun	12840800
Erlotinib (Tarceva): an update on the clinical trial program.	2003 Jun	12840799
Pharmacokinetics and pharmacodynamics: maximizing the clinical potential of Erlotinib (Tarceva).	2003 Jun	12840798
Preclinical studies with Erlotinib (Tarceva).	2003 Jun	12840797
Erlotinib (Tarceva): a promising drug targeting epidermal growth factor receptor tyrosine kinase.	2003 Jun	12820772
Development of the epidermal growth factor receptor inhibitor OSI-774.	2003 Jun	12802792
Developing inhibitors of the epidermal growth factor receptor for cancer treatment.	2003 Jun 18	12813169
Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment.	2003 Mar	12653668
Role of docetaxel in the treatment of newly diagnosed advanced ovarian cancer.	2003 May 15	12743129
[Therapeutic implications of epidermal growth factor receptor in lung cancer].	2003 Nov	14763145
[Inhibitors of epidermal growth factor receptor and colorectal cancer].	2003 Nov	14763144
Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome?	2003 Nov	14682120
Clinical experience with the HER1/EGFR tyrosine kinase inhibitor erlotinib.	2003 Nov	14682119
Epidermal growth factor receptor tyrosine kinase inhibitors in late stage clinical trials.	2003 Nov	14662002
Defining the role of the epidermal growth factor receptor in pancreatic cancer grown in vitro.	2003 Nov	14599602
Pharmacology of oral chemotherapy agents.	2003 Nov-Dec	14705495
Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways.	2003 Oct	14599084
Receptor-guided alignment-based comparative 3D-QSAR studies of benzylidene malonitrile tyrphostins as EGFR and HER-2 kinase inhibitors.	2003 Oct 23	14561085
Liquid-chromatographic determination of erlotinib (OSI-774), an epidermal growth factor receptor tyrosine kinase inhibitor.	2003 Oct 25	14552829
Epidermal growth factor receptor inhibitors, gefitinib and erlotinib (Tarceva , OSI-774), in the treatment of bronchioloalveolar carcinoma.	2003 Sep	14596689
Gateways to clinical trials.	2003 Sep	14571286
Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition.	2003 Sep-Oct	14666659
Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy.	2004	14977353
HER1/EGFR targeting: refining the strategy.	2004	14755015
Lung cancer: looking ahead in 2004.	2004 Jan	14967070
Synthesis and SAR of potent EGFR/erbB2 dual inhibitors.	2004 Jan 5	14684309
Gateways to clinical trials.	2004 Jan-Feb	14988742
The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer.	2004 Jun 15	15217965
Current data and ongoing trials in patients with recurrent non-small-cell lung cancer.	2004 May	15217532

Patents

Sample Use Guides

In Vivo Use Guide

The dose for NSCLC is 150 mg/day. The dose for pancreatic cancer is 100 mg/day. All doses of TARCEVA should be taken on an empty stomach at least one hour before or two hours after food

Route of Administration: Oral

In Vitro Use Guide

Erlotinib (20 µM) inhibited 33.8% of the growth of T. gondii

Name

Type

Language

ERLOTINIB

Official Name

English

CP-358,774

Preferred Name

English

N-(3-ETHYNYLPHENYL)-6,7-BIS(2-METHOXYETHOXY)QUINAZOLIN-4-AMINE

Systematic Name

English

CP-358774

Code

English

RG-1415

Code

English

ERLOTINIB [EMA EPAR]

Common Name

English

R-1415

Code

English

Erlotinib [WHO-DD]

Common Name

English

CP-35877401

Code

English

ERLOTINIB [MI]

Common Name

English

erlotinib [INN]

Common Name

English

ERLOTINIB [VANDF]

Common Name

English

4-QUINAZOLINAMINE, N-(3-ETHYNYLPHENYL)-6,7-BIS(2-METHOXYETHOXY)-

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2167