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184475-35-2 (Gefitinib)

1

Identification

Gefitinib Gefitinib
Name Gefitinib
Formula C22H24ClFN4O3
MW 446.9
CAS No. 184475-35-2
EINECS
Smiles ClC(C=C1NC2=NC=NC3=C2C=C(OCCCN4CCOCC4)C(OC)=C3)=C(C=C1)F
Synonyms N-(3-Chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine
InChI 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)
2

Introduction

Gefitinib(ZD1839) is an EGFR inhibitor, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells.

Background Information

Selective EGFR inhibitor ......by AOBIOUS INC
Gefitinib is an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and has been shown to increase phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in HaCaT cells. The Gefitinib selective inhibitor of EGFR tyrosine kinase (IC50 = 23 - 79 nM). Shows minimal activity against ErbB2, KDR, c-flt, PKC, MEK and ERK-2. Blocks EGFR autophosphorylation and inhibits tumor growth in mice. ......by Affix Scientific

Gefitinib, also known as ZD1839 or Iressa, is a potent and orally-bioavailable small-molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase with 50% inhibition concentration IC50 values of 0.033 μM and 0.027 μM in A431 membrane prep and baculovirus lysate respectively. Gefitinib binds to the kinase ATP binding site of EGFR interfering with the binding of adenosine triphosphate, which suppresses the EGFR tyrosine kinase activity and resultant signal transduction of EGFR. Gefitinib exhibits anti-angiogenic activities in a wide range of human tumor types, including head and neck, prostate, breast, ovarian, colon, small-cell lung and non-small-cell lung cancer. Moreover, geftinib has also been found to reduce proliferation, induce cell cycle arrest and increase apoptosis.

Reference

M. Ranson and S. Wardell. Gefitinib, a novel, orally administered agent for the treatment of cancer. Journal of Clinical Pharmacy and Therapeutics (2004) 29, 95-103

Joachim Von Pawel. Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors. Bull Cancer 2004; 91(5): E70-E76

......by Apexbio Technology LLC
Gefitinib effectively inhibits all tyrosine phosphorylation sites on EGFR in both the high and low-EGFR-expressing cell lines including NR6, NR6M and NR6W cell lines. The phosphorylation sites Tyr1173 and Tyr992 are less sensitive requiring higher concent ......by BOC Sciences
EGFR tyrosine kinase inhibitor that binds to the ATP-binding site of the enzyme. The functions of the EGFR tyrosine kinase in activating the Ras signal transduction cascade and malignant cell growth are thus inhibited. It has been shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways in gefitinib-sensitive non-small cell lung cancers. These mutations tend to increase sensitivity to tyrosine kinase inhibitors including gefitinib and erlotinib. The adenocarcinoma subset of non-small cell lung cancer histologies often have these mutations, which are commonly found in Asians, women, and non-smokers. Pao, W., et al. "EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib." Proc. Natl. Acad. Sci. USA 101: 13306-13311 (2004). Sordella, R., et al. "Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways." Science 305: 1163-1167 (2004). The IC50 values for gefitinib for inhibiting HT-29 and LoVo cell growth were 23.6 - >100 µM and 7.3 - 48.5 µM, respectively, when the exposure times are from 18 hours to 3 days. A time-dependent reduction in IC50 was observed for gefitinib, with the IC50 after 3 days of exposure being 4-8 fold less after 18 hours of exposure. Azzariti, A., et al. "Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib (Iressa™) and to the antiangiogenic agent ZD6474: Cytotoxic and biomolecular effects." World J. Gastroenterol. 12: 5140-5147 (2006). Gefitinib was found to be a potent inhibitor of EGFR kinase (Ki = 0.40 nM), but much weaker against ErbB-2 kinase (Ki = 870 nM) and ErbB-4 kinase (Ki = 1.1 µM). Wood, E.R., et al. "A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib), Relationships among Protein Conformation, Inhibitor Off-Rate, and Receptor Activity in Tumor Cells." Cancer Res. 64: 6652-6659 (2004). The IC50 of gefitinib for cells grown in the absence (IC50 = 8.8 µM) of EGF is >100-fold weaker than that in the presence (IC50 = 0.054 µM) of EGF. Gefitinib selectively inhibited EGF-stimulated growth of HUVECs (IC50 = 0.03 - 0.1 µM) compared with FGF- or VEGF-stimulated growth (IC50 = 1 - 3 µM for both). Enzyme kinetic studies were used to determine the characteristics of gefitinib inhibition of EGFR tyrosine kinase. Gefitinib is a competitive inhibitor with respect to ATP (Ki = 2.1 nM) when the peptide substrate concentration was fixed at 2 mM (6-fold higher than the Km) and the ATP concentration was varied. Gefitinib showed noncompetitive kinetics (Ki = 15.0 nM) when the ATP concentration was 50 µM (6-fold higher than the Km) and the peptide concentration was varied. Wakeling, A.E., et al. "ZD1839 (Iressa), An Orally Active Inhibitor of Epidermal Growth Factor Signaling with Potential for Cancer Therapy." Cancer Res. 62: 5749-5754 (2002). ......by LC Laboratoies
Gefitinib is an inhibitor that specifically binds and inhibits the EGFR tyrosine kinase, with the IC50 value of 2-37 nM in NR6wtEGFR cells. ......by MedChemexpress Co., Ltd.
Gefitinib (ZD-1839) is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively. ......by Selleck Chemicals LLC
Gefitinib (originally coded ZD1839) is a drug used in the treatment of certain types of cancer. Acting in a similar manner to erlotinib (marketed as Tarceva), gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa. ......by Target Molecule Corp.
3

Protocol(Only for Reference)

Cell Experiment

Cell lines BT-474 cells
Conditions 1 μM, 24 hours
Method A 24-h treatment of BT-474 cells with 1 μM ZD1839 increased the G1 fraction from 74 to 88% and reduced the proportion of cells in S from 15 to 4%. Simultaneous with the accumulation of cells in G1 was complete elimination of both active Akt and MAPK, as measured with phosphospecific antibodies, without changes in the content of total Akt and MAPK. Consistent with the inhibition of Akt activity, phosphorylation of GSK-3β, a target of the Akt kinase, was reduced. Cyclin D1 and Cdk4 were also reduced, whereas protein levels of the Cdk inhibitor p27 were up-regulated.
Source Apexbio Technology LLC
Cell lines NR6, NR6M and NR6W cells
Conditions 0-2 μM; 72 hours
Method Exponentially growing cells including NR6, NR6M, NR6M and NR6W cells are seeded in sextuple in 96-well plates at a concentration of 2000 cells/well, allowed to adhere and subsequently washed in PBS and incubated overnight in medium containing 0.5% FCS. Cells are then treated with varying concentrations (0-2 μM) of Gefitinib or the solute control DMSO and EGF. The optimal EGF concentration for inducing proliferation of NR6wtEGFR and NR6W cells has previously been determined and hence NR6wtEGFR and NR6W cells are supplemented with 10 nM and 0.1 nM EGF, respectively. EGF is not added to NR6 and NR6M cells. After 72 hours the amount of cells are measured by performing a MTT proliferation assay.
Source Selleck Chemicals LLC

Animal Experiment

Animal Models Female Balb/C athymic nude mice injected with BT-474 cells
Dosage Form Oral administration, 200 mg/kg/day
Applications Mice were randomly allocated to either no treatment, ZD1839, Herceptin, or the combination. ZD1839 completely prevented tumor growth but did not induce complete remissions. Herceptin alone induced complete remission in two of seven, whereas the combination resulted in three of eight complete responses. No mice exhibited treatment-related toxicity. Three mice treated with ZD1839 plus Herceptin, in which tumors regressed completely, remained tumor free for > 6 months after discontinuation of therapy and had no detectable tumor at necropsy.
Source Apexbio Technology LLC
Animal Models Female nude mice (cba nu/nu) aged 8–10 weeks are intra-dermal injected with LoVo cells.
Dosage 100 mg/kg
Formulation 0.5% polysorbate
Administration Once daily by oral administration (0.1 mL/10 g body weight) for 14 days
Source Selleck Chemicals LLC
4

Physical and Chemical Properties

Appearance:White to off-white Solid EBNumber:EB000029042

Storage condition

Up to one week at 4°C or six months at -20°C. by Affix Scientific
Store at -20°C by Apexbio Technology LLC
Store at or below -20 oC. by LC Laboratoies

Solubility

Soluble in DMSO > 10 mM by Apexbio Technology LLC
Soluble in DMSO, up to about 100 mg/mL; very poorly soluble in water or ethanol. by LC Laboratoies
DMSO ≥86mg/mL Water <1.2mg/mL Ethanol ≥10mg/mL by MedChemexpress Co., Ltd.
(25°C) * In vitro DMSO 89 mg/mL (199.14 mM); Ethanol4 mg/mL (8.95 mM); Water<1 mg/mL (<1 mM); In vivo 5% DMSO+Corn oil2.5mg/mL by Selleck Chemicals LLC
5

Mechanism and Indication

Signaling Pathways JAK/STAT Signaling Protein Tyrosine Kinase/RTK Autophagy
Target EGFR Autophagy
Research Area Cancer
Indications
6

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
Gefitinib - Launched
7

Safety Data of Gefitinib

8

Spectral Information

9

Suppliers List

Company Price and Availability Country/Region
AOBIOUS INC 1mg/USD9() USA
Affix Scientific 1g/USD955(In stock) USA
Apexbio Technology LLC USA
BOC Sciences
CHEMSCENE, LLC 100mg/USD60();500mg/USD72() USA
Hangzhou Hexo Chemtech Co., Ltd. China
Hunan OUYA Biological Co., Ltd. China
Jintan Yufan Medicine Raw Materials Co., Ltd. China
LC Laboratoies 1g/USD59(In stock);2g/USD98(In stock);5g/USD177(In stock);10g/USD265(In stock);20g/USD490(In stock);25g/USD585(In stock);50g/USD890(In stock) USA
MedChemexpress Co., Ltd. 100mg/USD60();500mg/USD72() USA
Nanjing Ange Pharmaceutical Co., Ltd. China
Nanjing Pharmaluxury Co., Ltd. China
Novelab Ltd. China
Selleck Chemicals LLC 100mg/USD147(In stock);10mM/1mLIn DMSO/USD191(In stock);250mg/USD270(In stock) USA
Shanghai Amadis Bio-Technology Co., Ltd CHINA
Shanghai Haoyuan Chemexpress Co., Ltd. 100mg/USD60();500mg/USD72() China
Taizhou Apler Chemical Industry Co., Ltd. China
Taizhou Huading Chemical Industry Co., Ltd. China
Taizhou Yongfeng Chemical Industry Co., Ltd. China
Target Molecule Corp. 10mg/USD37();50mg/USD75();100mg/USD125();250mg/USD198() USA
10

Related Products

Other Forms of 184475-35-2

Name CAS No Formula MW
Gefitinib (hydrochloride) 184475-55-6 C22H25Cl2FN4O3 483.36
Gefitinib (Dihydrochloride) 184475-56-7 C22H26Cl3FN4O3 519.8242
Gefitinib (D8) 857091-32-8 C22H16D8ClFN4O3 454.95

Recommended Compounds in EGFR Autophagy

Name CAS No Formula MW
Ginsenoside Rh2 78214-33-2 C36H62O8 622.87
Mutated EGFR-IN-1 1421372-66-8 C25H31N7O 445.56
AZD-9291 (mesylate) 1421373-66-1 C29H37N7O5S 595.71
Mutant EGFR inhibitor 1421373-62-7 C27H30ClN7O2 520.03
AZD-9291 1421373-65-0 C28H33N7O2 499.61
WHI-P180 (hydrochloride) 153437-55-9 C16H16ClN3O3 333.77
WHI-P180 211555-08-7 C16H15N3O3 297.31
Gefitinib (hydrochloride) 184475-55-6 C22H25Cl2FN4O3 483.36
Erlotinib (mesylate) 248594-19-6 C23H27N3O7S 489.54
BGB-102 807640-87-5 C22H25BrN4O2 457.36
Poziotinib 1092364-38-9 C23H21Cl2FN4O3 491.34
CO-1686 (hydrobromide) 1446700-26-0 C27H29BrF3N7O3 636.46
CO-1686 1374640-70-6 C27H28F3N7O3 555.55
CNX-2006 1375465-09-0 C26H27F4N7O2 545.53
PD168393 194423-15-9 C17H13BrN4O 369.2153
AG 18 118409-57-7 C10H6N2O2 186.17
Afatinib (dimaleate) 850140-73-7 C32H33ClFN5O11 718.08
Chrysophanol 481-74-3 C15H10O4 254.2375
AG-1478 153436-53-4 C16H14ClN3O2 315.75
Mubritinib 366017-09-6 C25H23F3N4O2 468.47

Recommended Compounds in Same Indication

Name CAS No Formula MW
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Route of Synthesis

12

References

[1]. Pedersen MW, et al. Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII. Br J Cancer. 2005 Oct 17;93(8):915-23.

[2]. Moasser MM, et al. The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 2001 Oct 1;61(19):7184-8.

[3]. Morgillo F, et al. Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin Cancer Res. 2013 Jul 1;19(13):3508-19.

[4]. Miyake K, et al. Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats. J Med Invest. 2012;59(1-2):174-85.

[5]. Nakamura Y, et al. Gefitinib increases serum concentrations of oral irinotecan and SN-38 without increasing the biliary concentration of SN-38 in rats. Chemotherapy. 2008;54(6):485-91.

[6]. Cantarini MV, et al. Relative bioavailability and safety profile of gefitinib administered as a tablet or as a dispersion preparation via drink or nasogastric tube: results of a randomized, open-label, three-period crossover study in healthy volunteers. Clin Ther. 2004 Oct;26(10):1630-6.

Protocol Reference

[1] Moulder S L, Yakes F M, Muthuswamy S K, et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer research, 2001, 61(24): 8887-8895.

......by Apexbio Technology LLC
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More Information

Gefitinib

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