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Purity: ≥98%
Icotinib (formerly known as BPI-2009; trade name Conmana), a side chain-cyclized form of erlotinib, is an orally available and specific EGFR inhibitor with potent anticancer activity. Icotinib was licensed in China in 2011 to treat non-small cell lung cancer (NSCLC). It shares structural similarities with erlotinib. With an IC50 of 5 nM, it inhibits all forms of EGFR, including EGFR(T790M), EGFR(L858R), EGFR(L861Q), and EGFR(T790M, L858R). Icotinib only demonstrated significant inhibitory activity against EGFR and its mutants when profiled using 88 kinases. Icotinib inhibits the proliferation of tumor cells and blocked EGFR-mediated intracellular tyrosine phosphorylation (IC50 = 45 nM) in the human epidermoid carcinoma A431 cell line. Icotinib showed strong dose-dependent antitumor effects in nude mice bearing different human tumor xenografts, according to in vivo studies. In mice, the medication was well tolerated at dosages up to 120 mg/kg/day without causing death or appreciable body weight loss while the mice were being treated. Gefitinib was used as an active control in a head-to-head randomized, double-blind phase III trial that was recently completed for patients with advanced non-small cell lung cancer (NSCLC) (Trial registration ID: NCT01040780). The information demonstrates that Icotinib outperformed Gefitinib in terms of safety and median progression-free survival (PFS), with Icotinib outperforming Gefitinib in terms of safety.
Targets |
EGFR (IC50 = 5 nM); EGFRL858R; EGFRL858R/T790M; EGFRT790M; EGFRL861Q
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ln Vitro |
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ln Vivo |
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Enzyme Assay |
The 2.4 ng/μL EGFR protein and 32 ng/μL Crk are combined in a 25 μL kinase reaction buffer that contains 1 μM cold ATP and 1 μCi32P-γ-ATP for the in vitro kinase assays. A 10-minute ice-based incubation period is used to incubate the mixture at 0, 0.5, 2.5, 12.5, or 62.5 nM of icotinib. A 20-minute curing period is then added. A 10% SDS-PAGE gel is used for electrophoresis to resolve the protein mixture following a 4-minute quench with SDS sample buffer at 100°C. In order to detect radioactivity, the dried gel is subsequently exposed. Software handles quantification[1].
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Cell Assay |
In RPMI-1640 medium containing 10% FBS, 1000 cells per well are seeded into 96-well plates. The cells are then grown at 37°C in an incubator with 5% CO2. After a day, Icotinib is added to the cells at 0, 0.78, 1.56, 3.125, 6.25, 12.5, or 25 μM for a full day. The calculation of cell proliferation involves deducting the average absorbance value on day 0 from the average absorbance value on day 4 [1].
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Animal Protocol |
Mice: In mice with A431, A549, H460, and HCT8 tumor xenografts, the effects of three doses of icotinib (30, 60, and 120 mg/kg/dose p.o. qd) on antitumor activity and survival are assessed. In these studies, a positive control group is given 30 mg/kg/dose intraperitoneally once a week[1].
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ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
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 |
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Toxicity/Toxicokinetics |
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. |
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References | ||
Additional Infomation |
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. 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. 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. Icotinib hydrochloride is a member of quinazolines. Icotinib Hydrochloride is the hydrochloride salt form of icotinib, 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, one of the leading compounds selected from our compound library, was found to be a potent and specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an IC(50) of 5 nM. When profiled with 88 kinases, Icotinib only showed meaningful inhibitory activity to EGFR and its mutants. Icotinib blocked EGFR-mediated intracellular tyrosine phosphorylation (IC(50)=45 nM) in the human epidermoid carcinoma A431 cell line and inhibits tumor cell proliferation. 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). The data shows that Icotinib was non-inferior to Gefitinib in terms of median progression free survival (PFS) and safety superior favor to Icotinib compared to Gefitinib.[1] |
Molecular Formula |
C22H21N3O4
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Molecular Weight |
391.42
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Exact Mass |
391.153
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Elemental Analysis |
C, 67.51; H, 5.41; N, 10.74; O, 16.35
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CAS # |
610798-31-7
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Related CAS # |
Icotinib Hydrochloride;1204313-51-8;Icotinib-d4;1567366-82-8
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PubChem CID |
22024915
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Appearance |
White to off-white solid powder
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Density |
1.3±0.1 g/cm3
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Boiling Point |
581.3±50.0 °C at 760 mmHg
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Flash Point |
305.3±30.1 °C
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Vapour Pressure |
0.0±1.6 mmHg at 25°C
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Index of Refraction |
1.649
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LogP |
1.88
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Hydrogen Bond Donor Count |
1
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Hydrogen Bond Acceptor Count |
7
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Rotatable Bond Count |
3
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Heavy Atom Count |
29
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Complexity |
553
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Defined Atom Stereocenter Count |
0
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SMILES |
O1C([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC2C([H])=C3C(C(=NC([H])=N3)N([H])C3=C([H])C([H])=C([H])C(C#C[H])=C3[H])=C([H])C1=2
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InChi Key |
QQLKULDARVNMAL-UHFFFAOYSA-N
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InChi Code |
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)
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Chemical Name |
N-(3-ethynylphenyl)-2,5,8,11-tetraoxa-15,17-diazatricyclo[10.8.0.014,19]icosa-1(12),13,15,17,19-pentaen-18-amine
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Synonyms |
BPI-2009; BPI2009; BPI 2009; BPI2009H; BPI-2009H; 610798-31-7; Conmana; BPI-2009; N-(3-ethynylphenyl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine; UNII-9G6U5L461Q; 9G6U5L461Q; ICOTINIB [WHO-DD]; BPI 2009H; Icotinib; Trade name: Conmana
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.39 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 0.5% CMC: 30mg/mL |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.5548 mL | 12.7740 mL | 25.5480 mL | |
5 mM | 0.5110 mL | 2.5548 mL | 5.1096 mL | |
10 mM | 0.2555 mL | 1.2774 mL | 2.5548 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT04206072 | Active Recruiting |
Drug: Icotinib Hydrochloride Tablets Drug: D-0316 Capsule |
Non-Small Cell Lung Cancer EGFR Gene Mutation |
Betta Pharmaceuticals Co., Ltd. | December 24, 2019 | Phase 2 Phase 3 |
NCT02448797 | Active Recruiting |
Drug: Icotinib Drug: Chemotherapy |
Non-small Cell Lung Cancer | Betta Pharmaceuticals Co., Ltd | June 8, 2015 | Phase 3 |
NCT02264210 | Recruiting | Drug: Icotinib | Lung Neoplasms Large Cell Lung Cancer |
Sun Yat-sen University | January 2015 | Phase 2 |
NCT06041776 | Recruiting | Drug: Befotertinib + Icotinib placebo Drug: Icotinib + Befotertinib placebo |
Adjuvant Therapy EGFR Sensitive Mutation |
Betta Pharmaceuticals Co., Ltd. | March 28, 2023 | Phase 3 |
NCT03992885 | Recruiting | Drug: Icotinib | Non-squamous Non-small Cell Lung Cancer |
Tianjin Medical University Cancer Institute and Hospital |
July 1, 2019 | Phase 3 |