Icotinib

Identification

Name
Icotinib
Accession Number
DB11737
Type
Small Molecule
Groups
Approved, 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 hydrochlorideJTD32I0J83 1204313-51-8PNNGXMJMUUJHAV-UHFFFAOYSA-N
Approved Prescription Products
Not Available
Approved Generic Prescription Products
Not Available
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Not Available
Brand mixtures
Not Available
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.

Structured Indications
Not Available
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
Not Available
Food Interactions
Not Available

References

Synthesis Reference
Not Available
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
ChemSpider
10762174
BindingDB
50391089
ChEMBL
CHEMBL2087361
Wikipedia
Icotinib
ATC Codes
Not Available
AHFS Codes
Not Available
PDB Entries
Not Available
FDA label
Not Available
MSDS
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentMalignant Neoplasm of Pancreas1
1CompletedTreatmentPsoriasis1
1RecruitingTreatmentMalignant Neoplasm of Pancreas1
1RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)1
1RecruitingTreatmentPsoriasis1
1WithdrawnTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1, 2CompletedTreatmentMetastatic Brain Tumors / Non-Small-Cell Lung Carcinoma (NSCLC)1
1, 2Unknown StatusTreatmentNasopharyngeal Carcinoma1
2Active Not RecruitingTreatmentNasopharyngeal Carcinoma1
2Active Not RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)2
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 carcinoma cell type unspecified stage IV1
2Not Yet RecruitingTreatmentMild to Moderate Psoriasis1
2Not Yet RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)1
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
2RecruitingTreatmentEsophageal Cancers1
2RecruitingTreatmentLung Cancers1
2RecruitingTreatmentLung, Carcinoma1
2RecruitingTreatmentMetastatic Brain Tumors / Non-Small-Cell Lung Carcinoma (NSCLC)1
2RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2RecruitingTreatmentNeurofibromatosis Type 2 / Vestibular Schwannomas1
2RecruitingTreatmentNon-Small-Cell Lung Cancer (NSCLC)2
2RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)9
2RecruitingTreatmentSquamous Cell Carcinoma of Esophagus1
2Unknown StatusTreatmentMetastatic Brain Tumors / Non-Small-Cell Lung Carcinoma (NSCLC)1
2Unknown StatusTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)3
3Active Not RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)2
3CompletedTreatmentBrain Metastasis / Non-Small-Cell Lung Carcinoma (NSCLC)1
3CompletedTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)2
3Enrolling by InvitationTreatmentCancers1
3RecruitingTreatmentAdenocarcinomas / EGFR Positive Non-small Cell Lung Cancer1
3RecruitingTreatmentLung Cancers1
3RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)2
4Active Not RecruitingTreatmentAdenocarcinomas / EGFR Positive Non-small Cell Lung Cancer1
4Active Not RecruitingTreatmentNeoplasms, Therapy-Associated1
4Active Not RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)1
4CompletedTreatmentNeoplasms, Lung1
4CompletedTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)1
4RecruitingTreatmentAdenocarcinomas / EGFR Positive Non-small Cell Lung Cancer2
4RecruitingTreatmentNon-Small-Cell Lung Cancer (NSCLC)2
4RecruitingTreatmentNon-Small-Cell Lung Carcinoma (NSCLC)2
4SuspendedTreatmentNon-Small-Cell Lung Carcinoma (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 LC-MS/MS Spectrum - 10V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 10V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, NegativePredicted 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. Wikipedia [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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. Wikipedia [Link]
Drug created on October 20, 2016 14:43 / Updated on September 01, 2017 12:12