Identification

Name
Icotinib
Accession Number
DB11737
Type
Small Molecule
Groups
Experimental, Investigational
Description

Icotinib is a potent and specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Icotinib was approved in China by the SFDA in June, 2011 and in January 2014, Beta Pharma, Inc. was given a “May Proceed” from the US FDA to conduct a Phase I study for the evaluation of icotinib as a treatment of EGFR+ Non-Small Cell Lung Cancer (NSCLC).

Structure
Thumb
Synonyms
  • BPI-2009
External IDs
BPI-2009
Product Ingredients
IngredientUNIICASInChI Key
Icotinib hydrochlorideJTD32I0J831204313-51-8PNNGXMJMUUJHAV-UHFFFAOYSA-N
Categories
UNII
9G6U5L461Q
CAS number
610798-31-7
Weight
Average: 391.427
Monoisotopic: 391.153206168
Chemical Formula
C22H21N3O4
InChI Key
QQLKULDARVNMAL-UHFFFAOYSA-N
InChI
InChI=1S/C22H21N3O4/c1-2-16-4-3-5-17(12-16)25-22-18-13-20-21(14-19(18)23-15-24-22)29-11-9-27-7-6-26-8-10-28-20/h1,3-5,12-15H,6-11H2,(H,23,24,25)
IUPAC Name
N-(3-ethynylphenyl)-7H,8H,10H,11H,13H,14H-1,4,7,10-tetraoxacyclododeca[2,3-g]quinazolin-4-amine
SMILES
C#CC1=CC=CC(NC2=NC=NC3=CC4=C(OCCOCCOCCO4)C=C23)=C1

Pharmacology

Indication

Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor, exhibits encouraging efficacy and tolerability in patients with advanced non-small-cell lung cancer (NSCLC) who failed previous chemotherapy.

Pharmacodynamics

In vitro: Icotinib inhibits EGFR activity in a dose-dependent manner, with an IC50 value of 5 nM and complete inhibition at 62.5 nM. Icotinib selectively solely inhibits the EGFR members including the wild type and mutants with inhibition efficacies of 61-99%. Icotinib blocks EGFR-mediated intracellular tyrosine phosphorylation in human epidermoid carcinoma A431 cells in a dose-dependent manner. Meanwhile, in the proliferation assay performed on A431, BGC-823, A549, H460, HCT8, KB and Bel-7402 cell lines, it was found that the relative sensitivity of cell lines to Icotinib is A431 > BGC-823 > A549 > H460 > KB > HCT8 and Bel-7402. Icotinib exhibits a broad spectrum of antitumor activity and it is especially effective against tumors expressing higher levels of EGFR. In vivo: In vivo studies demonstrated that Icotinib exhibited potent dose-dependent antitumor effects in nude mice carrying a variety of human tumor-derived xenografts. The drug was well tolerated at doses up to 120 mg/kg/day in mice without mortality or significant body weight loss during the treatment. A head to head randomized, double blind phase III trial using Gefitinib as an active control for patients with advanced non-small cell lung cancer (NSCLC) was finished recently (Trial registration ID: NCT01040780).

Mechanism of action

Icotinib is a quinazoline derivative that binds reversibly to the ATP binding site of the EGFR protein, preventing completion of the signal transduction cascade. It is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). EGFR is an oncogenic driver and patients with somatic mutations, particularly an exon 19 deletion or exon 21 L858R mutation, within the tyrosine kinase domain have activating mutations that lead to unchecked cell proliferation. Over expression of EGFR causes inappropriate activation of the anti-apoptotic Ras signaling pathway, found in many different types of cancer.

TargetActionsOrganism
UEpidermal growth factor receptor
antagonist
Human
Absorption

Bioavailability = 52%

Volume of distribution

the volume of distribution was calculated as Vz/F = 115.00 ± 63.26 l

Protein binding

Icotinib binds to Sudlow's site I in subdomain IIA of Human Serum Albumin (HSA) molecule, resulting in the formation of icotinib-HSA complexes.

Metabolism

Hepatic (mainly CYP3A4, less CYP1A2)

Route of elimination

>90% via faeces, 9% via urine

Half life

5.5 hrs

Clearance

the clearance was calculated as CL/F = 13.30 ± 4.78 l/h

Toxicity

The most common toxicities reported are skin-related events and diarrhea.

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

Interactions

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

References

General References
  1. Tan F, Shi Y, Wang Y, Ding L, Yuan X, Sun Y: Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer. Future Oncol. 2015;11(3):385-97. doi: 10.2217/fon.14.249. [PubMed:25675121]
  2. Tan F, Shen X, Wang D, Xie G, Zhang X, Ding L, Hu Y, He W, Wang Y, Wang Y: Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies. Lung Cancer. 2012 May;76(2):177-82. doi: 10.1016/j.lungcan.2011.10.023. Epub 2011 Nov 22. [PubMed:22112293]
  3. Liu D, Jiang J, Zhang L, Tan F, Wang Y, Hu P: Metabolite characterization of a novel anti-cancer agent, icotinib, in humans through liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Rapid Commun Mass Spectrom. 2011 Aug 15;25(15):2131-40. doi: 10.1002/rcm.5061. [PubMed:21732454]
  4. Guan YS, He Q, Li M: Icotinib: activity and clinical application in Chinese patients with lung cancer. Expert Opin Pharmacother. 2014 Apr;15(5):717-28. doi: 10.1517/14656566.2014.890183. Epub 2014 Mar 4. [PubMed:24588695]
  5. Zhang HX, Xiong HX, Li LW: Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method. Spectrochim Acta A Mol Biomol Spectrosc. 2016 May 15;161:88-94. doi: 10.1016/j.saa.2016.02.014. Epub 2016 Feb 23. [PubMed:26963729]
  6. Icotonib approval [Link]
  7. Efficacy and safety of icotinib as first-line therapy in patients with advanced non-small-cell lung cancer [Link]
  8. Wikipedia [Link]
External Links
PubChem Compound
22024915
PubChem Substance
347828095
ChemSpider
10762174
BindingDB
50391089
ChEMBL
CHEMBL2087361
PharmGKB
PA166114460
Wikipedia
Icotinib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentMalignant Neoplasm of Pancreas1
1CompletedTreatmentPsoriasis1
1RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1RecruitingTreatmentMalignant Neoplasm of Pancreas1
1RecruitingTreatmentPsoriasis1
1WithdrawnTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1, 2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Metastatic Brain Tumors1
1, 2CompletedTreatmentNasopharyngeal Carcinoma1
2Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
2Active Not RecruitingTreatmentNasopharyngeal Carcinoma1
2CompletedTreatmentLung Cancers / Metastatic Cancers1
2Not Yet RecruitingTreatmentAdenocarcinoma of the Lung1
2Not Yet RecruitingTreatmentAdenocarcinoma of the Lung / EGFR Positive Non-small Cell Lung Cancer1
2Not Yet RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2Not Yet RecruitingTreatmentLung carcinoma cell type unspecified stage IV1
2Not Yet RecruitingTreatmentLung, Carcinoma1
2Not Yet RecruitingTreatmentSquamous Cell Carcinoma of Lung1
2RecruitingTreatmentAdenocarcinoma of the Lung1
2RecruitingTreatmentAdenocarcinoma of the Lung / Adenosquamous Cell Lung Cancer / Large Cell Lung Cancer / Neoplasm, Bronchial / Neoplasms, Lung / Squamous Cell Carcinoma of Lung / Stage IB Non-small Cell Lung Cancer1
2RecruitingTreatmentAdenocarcinomas of the Gastroesophageal Junction / Oesophageal Carcinoma1
2RecruitingTreatmentEGF-R Positive Non-Small Cell Lung Cancer1
2RecruitingTreatmentEGFR Gene Mutations / Non Small Cell Lung Cancer Stage IIIA / Non Small Cell Lung Cancer Stage IIIB1
2RecruitingTreatmentEsophageal Cancers1
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)11
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Metastatic Brain Tumors1
2RecruitingTreatmentLung Cancers1
2RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2RecruitingTreatmentMild to Moderate Psoriasis1
2RecruitingTreatmentNeurofibromatosis Type 2 / Vestibular Schwannomas1
2RecruitingTreatmentPlasma EGFR Mutation-positive Lung Cancer1
2RecruitingTreatmentSquamous Cell Carcinoma of Esophagus1
2Unknown StatusTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)3
2Unknown StatusTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Metastatic Brain Tumors1
3Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
3CompletedTreatmentBrain Metastasis / Lung Cancer Non-Small Cell Cancer (NSCLC)1
3CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
3Enrolling by InvitationTreatmentMalignancies1
3RecruitingTreatmentAdenocarcinomas / EGFR Positive Non-small Cell Lung Cancer1
3RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
3RecruitingTreatmentLung Cancers1
4Active Not RecruitingTreatmentAdenocarcinomas / EGFR Positive Non-small Cell Lung Cancer1
4Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
4Active Not RecruitingTreatmentNeoplasms, Therapy-Associated1
4CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
4CompletedTreatmentNeoplasms, Lung1
4RecruitingTreatmentAdenocarcinomas / EGFR Positive Non-small Cell Lung Cancer2
4RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)4
4SuspendedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0126 mg/mLALOGPS
logP2.88ALOGPS
logP3.03ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)16.14ChemAxon
pKa (Strongest Basic)4.62ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area74.73 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity105.82 m3·mol-1ChemAxon
Polarizability42.08 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolinamines
Alternative Parents
Aniline and substituted anilines / Aminopyrimidines and derivatives / Alkyl aryl ethers / Imidolactams / Heteroaromatic compounds / Secondary amines / Oxacyclic compounds / Dialkyl ethers / Azacyclic compounds / Acetylides
show 2 more
Substituents
Quinazolinamine / Aniline or substituted anilines / Alkyl aryl ether / Aminopyrimidine / Monocyclic benzene moiety / Pyrimidine / Benzenoid / Imidolactam / Heteroaromatic compound / Dialkyl ether
show 13 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
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
References
  1. MedChem Express [Link]

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
References
  1. Zhang T, Zhang K, Ma L, Li Z, Wang J, Zhang Y, Lu C, Zhu M, Zhuang X: Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction. J Pharm Sci. 2018 Apr;107(4):979-983. doi: 10.1016/j.xphs.2017.12.007. Epub 2017 Dec 14. [PubMed:29247736]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Data supporting this enzyme action are limited to an in vitro study.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Zhang T, Zhang K, Ma L, Li Z, Wang J, Zhang Y, Lu C, Zhu M, Zhuang X: Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction. J Pharm Sci. 2018 Apr;107(4):979-983. doi: 10.1016/j.xphs.2017.12.007. Epub 2017 Dec 14. [PubMed:29247736]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Oxygen binding
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 oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Zhuang X, Zhang T, Yue S, Wang J, Luo H, Zhang Y, Li Z, Che J, Yang H, Li H, Zhu M, Lu C: Allosteric activation of midazolam CYP3A5 hydroxylase activity by icotinib - Enhancement by ketoconazole. Biochem Pharmacol. 2016 Dec 1;121:67-77. doi: 10.1016/j.bcp.2016.09.012. Epub 2016 Sep 22. [PubMed:27666601]
  2. Zhang T, Zhang K, Ma L, Li Z, Wang J, Zhang Y, Lu C, Zhu M, Zhuang X: Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction. J Pharm Sci. 2018 Apr;107(4):979-983. doi: 10.1016/j.xphs.2017.12.007. Epub 2017 Dec 14. [PubMed:29247736]

Drug created on October 20, 2016 14:43 / Updated on November 02, 2018 09:01