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Icotinib

Icotinib structure

CAS No:
610798-31-7
Formula:
C22H21N3O4
Chemical Name:
Icotinib
Synonyms:
[1,4,7,10]Tetraoxacyclododecino[2,3-g]quinazolin-4-amine,N-(3-ethynylphenyl)-7,8,10,11,13,14-hexahydro-;N-(3-Ethynylphenyl)-7,8,10,11,13,14-hexahydro[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine;Icotinib;BPI 2009H;1640118-92-8
Categories:
Biochemical Engineering > Inhibitors

Description

Icotinib (BPI-2009) is a potent and specific EGFR inhibitor with an IC50 of 5 nM; also inhibits mutant EGFRL858R, EGFRL858R/T790M, EGFRT790M and EGFRL861Q.

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).|Icotinib is an orally available quinazoline-based inhibitor of epidermal growth factor receptor (EGFR), with potential antineoplastic activity. Icotinib selectively inhibits the wild-type and several mutated forms of EGFR tyrosine kinase. This may lead to an inhibition of EGFR-mediated signal transduction and may inhibit cancer cell proliferation. EGFR, a receptor tyrosine kinase, has been upregulated in a variety of cancer cell types.

Icotinib Basic Attributes

Molecular Weight：

391.43

Exact Mass：

391.42

EC Number：

1592732-453-0

UNII：

9G6U5L461Q

DSSTox ID：

DTXSID20209952

NCI Thesaurus Code：

C138996

ATC Code：

L - Antineoplastic and immunomodulating agents

HScode：

29339900

Characteristics

PSA：

74.7

XLogP3：

3.1

Density：

1.3±0.1 g/cm3

Boiling Point：

581℃

Flash Point：

305℃

Refractive Index：

1.649

Toxicity

Toxicity Summary：

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

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.

Drug Information

Drug 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.

Pharmacology：

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).

Absorption：

Bioavailability = 52%|>90% via faeces, 9% via urine|the volume of distribution was calculated as Vz/F = 115.00 ± 63.26 l|the clearance was calculated as CL/F = 13.30 ± 4.78 l/h

Metabolism/Metabolites：

Hepatic (mainly CYP3A4, less CYP1A2)

Biological Half-Life：

5.5 hrs

Mechanism of Action：

Icotinib is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) which binds reversibly to the ATP binding site of the EGFR protein, preventing completion of the signal transduction cascade. EGFR is an oncogenic receptor and patients with activating somatic mutations, such as an exon 19 deletion or exon 21 L858R mutation, within the tyrosine kinase domain display unchecked cell proliferation.

MeSH Entry Terms：

4-((3-ethynylphenyl)amino)-6,7-benzo-12-crown-4-quinazoline

Icotinib Use and Manufacturing

Icotinib is a potent and specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with IC50 of 5 nM.

Computed Properties

Molecular Weight:391.4
XLogP3:3.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:3
Exact Mass:391.15320616
Monoisotopic Mass:391.15320616
Topological Polar Surface Area:74.7
Heavy Atom Count:29
Complexity:553
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

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Icotinib610798-31-7

CAS No.: 610798-31-7

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Content: 99%

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