Gefitinib
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MedKoo CAT#: 100140

CAS#: 184475-35-2

Description: Gefitinib, also known as ZD1839, is an anilinoquinazoline with antineoplastic activity. Gefitinib inhibits the catalytic activity of numerous tyrosine kinases including the epidermal growth factor receptor (EGFR), which may result in inhibition of tyrosine kinase-dependent tumor growth. Specifically, this agent competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction. Gefitinib may also induce cell cycle arrest and inhibit angiogenesis. It is marketed by AstraZeneca and Teva.


Chemical Structure

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Gefitinib
CAS# 184475-35-2

Theoretical Analysis

MedKoo Cat#: 100140
Name: Gefitinib
CAS#: 184475-35-2
Chemical Formula: C22H24ClFN4O3
Exact Mass: 446.1521
Molecular Weight: 446.9
Elemental Analysis: C, 59.13; H, 5.41; Cl, 7.93; F, 4.25; N, 12.54; O, 10.74

Price and Availability

Size Price Availability Quantity
50.0mg USD 90.0 Ready to ship
1.0g USD 150.0 Ready to ship
2.0g USD 250.0 Ready to ship
5.0g USD 550.0 Ready to ship
10.0g USD 950.0 Ready to ship
20.0g USD 1650.0 Ready to ship
50.0g USD 3650.0 Ready to ship
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Synonym: ZD 1839; ZD1839; ZD-1839; Gefitinib; US brand name: Iressa.

IUPAC/Chemical Name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine

InChi Key: XGALLCVXEZPNRQ-UHFFFAOYSA-N

InChi Code: InChI=1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)

SMILES Code: COC1=CC2=NC=NC(NC3=CC=C(F)C(Cl)=C3)=C2C=C1OCCCN4CCOCC4

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: EGFR tyrosine kinase inhibitor with IC50 of 33 nM.
In vitro activity: Gefitinib extensively inhibited transcription of genes in JAK-STAT and MAPK/ERK pathways. Both siC1-M2 and gefitinib inhibited the phosphorylation of multiple signaling kinases in these signaling pathways, indicating that gefitinib inhibited JAK-STAT and MAPK/ERK pathways activated by C1-M2 fusion. These results suggest that gefitinib simultaneously represses phosphorylation of multiple key signaling proteins which are activated in MEC, in part by C1-M2 fusion. Gefitinib-repressed kinase phosphorylation explains the transcriptional repression of genes in JAK-STAT and MAPK/ERK pathways. Reference: Curr Cancer Drug Targets. 2019;19(10):796-806. https://www.eurekaselect.com/168737/article
In vivo activity: M2-like polarized tumor-associated macrophages (TAMs) play a pivotal role in promoting cancer cell growth, invasion, metastasis and angiogenesis. The relevance of macrophage polarization and the antitumor effect of gefitinib in Lewis Lung cancer (LLC) was investigated in vivo. In LLC mice metastasis model, oral administration of gefitinib (75 mg·kg-1·d-1, for 21 d) significantly reduced the number of lung metastasis nodules, down-regulated the expression of M2 marker genes and the percentages CD206+ and CD68+ macrophages in tumor tissues. These results demonstrated that gefitinib effectively inhibits M2-like polarization in vivo, revealing a novel potential mechanism for the chemopreventative effect of gefitinib. Reference: Acta Pharmacol Sin. 2017 Nov;38(11):1501-1511. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672074/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 20.0 44.75
DMSO 50.92 113.94
DMSO:PBS (pH 7.2) (1:1) 0.5 1.12
Ethanol 2.92 6.53

Preparing Stock Solutions

The following data is based on the product molecular weight 446.9 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Takenaka T, Nakai S, Katayama M, Hirano M, Ueno N, Noguchi K, Takatani-Nakase T, Fujii I, Kobayashi SS, Nakase I. Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells. Int J Pharm. 2019 Dec 15;572:118762. doi: 10.1016/j.ijpharm.2019.118762. Epub 2019 Oct 11. PMID: 31610280; PMCID: PMC6899172. 2. Wu Y, He Z, Li S, Tang H, Wang L, Yang S, Dong B, Qin J, Sun Y, Yu H, Zhang Y, Zhang Y, Guo Y, Wang Q. Gefitinib Represses JAK-STAT Signaling Activated by CRTC1-MAML2 Fusion in Mucoepidermoid Carcinoma Cells. Curr Cancer Drug Targets. 2019;19(10):796-806. doi: 10.2174/1568009619666190103122735. PMID: 30605061. 3. Tariq M, Zhang JQ, Liang GK, He QJ, Ding L, Yang B. Gefitinib inhibits M2-like polarization of tumor-associated macrophages in Lewis lung cancer by targeting the STAT6 signaling pathway. Acta Pharmacol Sin. 2017 Nov;38(11):1501-1511. doi: 10.1038/aps.2017.124. Epub 2017 Oct 12. PMID: 29022575; PMCID: PMC5672074.
In vitro protocol: 1. Takenaka T, Nakai S, Katayama M, Hirano M, Ueno N, Noguchi K, Takatani-Nakase T, Fujii I, Kobayashi SS, Nakase I. Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells. Int J Pharm. 2019 Dec 15;572:118762. doi: 10.1016/j.ijpharm.2019.118762. Epub 2019 Oct 11. PMID: 31610280; PMCID: PMC6899172. 2. Wu Y, He Z, Li S, Tang H, Wang L, Yang S, Dong B, Qin J, Sun Y, Yu H, Zhang Y, Zhang Y, Guo Y, Wang Q. Gefitinib Represses JAK-STAT Signaling Activated by CRTC1-MAML2 Fusion in Mucoepidermoid Carcinoma Cells. Curr Cancer Drug Targets. 2019;19(10):796-806. doi: 10.2174/1568009619666190103122735. PMID: 30605061.
In vivo protocol: 1. Tariq M, Zhang JQ, Liang GK, He QJ, Ding L, Yang B. Gefitinib inhibits M2-like polarization of tumor-associated macrophages in Lewis lung cancer by targeting the STAT6 signaling pathway. Acta Pharmacol Sin. 2017 Nov;38(11):1501-1511. doi: 10.1038/aps.2017.124. Epub 2017 Oct 12. PMID: 29022575; PMCID: PMC5672074.

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1: Marech I, Vacca A, Gnoni A, Silvestris N, Lorusso V. Surgical resection of locally advanced epidermal growth factor receptor (EGFR) mutated lung adenocarcinoma after gefitinib and review of the literature. Tumori. 2013 Sep-Oct;99(5):e241-4. doi: 10.1700/1377.15324. Review. PubMed PMID: 24362878.

2: Chen X, Liu Y, Røe OD, Qian Y, Guo R, Zhu L, Yin Y, Shu Y. Gefitinib or erlotinib as maintenance therapy in patients with advanced stage non-small cell lung cancer: a systematic review. PLoS One. 2013;8(3):e59314. doi: 10.1371/journal.pone.0059314. Epub 2013 Mar 21. Review. PubMed PMID: 23555654; PubMed Central PMCID: PMC3605444.

3: Biaoxue R, Shuanying Y, Wei L, Wei Z, Zongjuan M. Maintenance therapy of gefitinib for non-small-cell lung cancer after first-line chemotherapy regardless of epidermal growth factor receptor mutation: a review in Chinese patients. Curr Med Res Opin. 2012 Oct;28(10):1699-708. doi: 10.1185/03007995.2012.728525. Epub 2012 Oct 2. Review. PubMed PMID: 22978775.

4: Erdem L, Giovannetti E, Leon LG, Honeywell R, Peters GJ. Polymorphisms to predict outcome to the tyrosine kinase inhibitors gefitinib, erlotinib, sorafenib and sunitinib. Curr Top Med Chem. 2012;12(15):1649-59. Review. PubMed PMID: 22978339.

5: Toda N, Fujimoto N, Kato T, Fujii N, Nakanishi G, Nagao T, Tanaka T. Erosive pustular dermatosis of the scalp-like eruption due to gefitinib: case report and review of the literature of alopecia associated with EGFR inhibitors. Dermatology. 2012;225(1):18-21. doi: 10.1159/000341528. Epub 2012 Aug 22. Review. PubMed PMID: 22922680.

6: Koma Y, Matsuoka H, Yoshimatsu H, Suzuki Y. Successful treatment with erlotinib after gefitinib-induced interstitial lung disease: a case report and literature review. Int J Clin Pharmacol Ther. 2012 Oct;50(10):760-4. doi: 10.5414/CP201759. Review. PubMed PMID: 22853866.

7: Wang F, Wang LD, Li B, Sheng ZX. Gefitinib compared with systemic chemotherapy as first-line treatment for chemotherapy-naive patients with advanced non-small cell lung cancer: a meta-analysis of randomised controlled trials. Clin Oncol (R Coll Radiol). 2012 Aug;24(6):396-401. doi: 10.1016/j.clon.2011.09.013. Epub 2011 Oct 22. Review. PubMed PMID: 22019482.

8: D'Incecco A, Cappuzzo F. Gefitinib for non-small-cell lung cancer treatment. Expert Opin Drug Saf. 2011 Nov;10(6):987-96. doi: 10.1517/14740338.2011.617738. Epub 2011 Sep 12. Review. PubMed PMID: 21905963.

9: Costanzo R, Piccirillo MC, Sandomenico C, Carillio G, Montanino A, Daniele G, Giordano P, Bryce J, De Feo G, Di Maio M, Rocco G, Normanno N, Perrone F, Morabito A. Gefitinib in non small cell lung cancer. J Biomed Biotechnol. 2011;2011:815269. doi: 10.1155/2011/815269. Epub 2011 May 23. Review. PubMed PMID: 21660144; PubMed Central PMCID: PMC3110340.

10: Gottschling S, Penzel R, Pelz T, Herpel E, Schnabel PA, Dyckhoff G, Thomas M, Kuhnt T. KRAS-mutation positive, metastatic tonsil carcinoma with cancer stem-like cell features and long-term response to gefitinib: a case report and review of the literature. J Clin Oncol. 2011 Jul 20;29(21):e616-9. doi: 10.1200/JCO.2011.34.5892. Epub 2011 May 9. Review. PubMed PMID: 21555681. 



Additional Information

 
According to http://en.wikipedia.org/wiki/Gefitinib, Gefitinib is the first selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase domain. Thus gefitinib is an EGFR inhibitor. The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature source. EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic Ras signalling cascade, eventually leading to uncontrolled cell proliferation. Research on gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways.  These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Of the types of non-small cell lung cancer histologies, adenocarcinoma is the type that most often harbors these mutations. These mutations are more commonly seen in Asians, women, and non-smokers (who also tend to more often have adenocarcinoma). Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited, and malignant cells are inhibited.
 
 
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy. While gefitinib has yet to be proven to be effective in other cancers, there is potential for its use in the treatment of other cancers where EGFR overexpression is involved.  In 2004, AstraZeneca informed the United States Food and Drug Administration (FDA) that a large randomized study failed to demonstrate a survival advantage for gefitinib in the treatment of non-small cell lung cancer (NSCLC). Whether progression-free survival is prolonged is not clear from this statement. AstraZeneca also withdrew their application to market gefitinib in Europe shortly after this announcement. Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib. Given the lack of survival advantage for gefitinib and the positive results for erlotinib, erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response).
Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy. While gefitinib has yet to be proven to be effective in other cancers, there is potential for its use in the treatment of other cancers where EGFR overexpression is involved.  In 2004, AstraZeneca informed the United States Food and Drug Administration (FDA) that a large randomized study failed to demonstrate a survival advantage for gefitinib in the treatment of non-small cell lung cancer (NSCLC). Whether progression-free survival is prolonged is not clear from this statement. AstraZeneca also withdrew their application to market gefitinib in Europe shortly after this announcement. Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib. Given the lack of survival advantage for gefitinib and the positive results for erlotinib, erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response).