EGFR INHIBITORS AGAINST THE CANCERS

by Selleckchem | Sep 12 2012

INHIBITION OF EGFR:
Among those few cascades which play an important role in the functioning of cells, epidermal growth factor receptor or EGFR pathway is one that has a vital role in growth, survival and proliferation of cells. The importance of this cascade can only be observed and understood in case of development of tumors and fatal diseases related to the uncontrolled cell growth caused by the improper regulation of EGFR signaling pathway. Over or mutated expression of the EGFR is associated with different types of cancers like colon, lung and breast cancers [1] and with multiform glioblastoma, anal and epithelial cancers. Therefore the treatment of these cancers by using the phenomenon of EGFR inhibition is found to be an attractive approach that led to magnify the importance of Erbb1 inhibitor [2]. These inhibitors along with their use in clinical processes, are also concerned with the survival of patients [3] and different EGFR antagonists and agonists are also in use for the revelation of various other cascades and the effects of EGFR pathway on them [4]. EGFR inhibitors can be obtained from any relevant supplier at a very normal cost.

VARIOUS EGFR INHIBITOR MOLECULES AND THEIR MECHANISM OF ACTION:
All these EGFR inhibitors have been developed by using very novel techniques like as screening library and they posses potent functions. The detailed knowledge about the discovery and function of EGFR molecule’s crystal structure has also increase the use of different EGFR inhibitors [5]. To assess the efficiency of a certain inhibitor molecule, one can perform different assays like fluorescent in situ hybridization or FISH [7], avidin biotin assay used for quantitation [6], Real time PCR [9], dual immmunocytochemical assay [8] and enzyme immunoassaysas well [10] and these chemical assays are usually perform before and after the implementation of inhibitor. The most famous specific EGFR inhibitor is Erlotinib having 4-anilinoquinazoline in its structure that has specific potential for EGFR [5]. Another EGFR inhibitor named Gefitinib has also shown remarkable success in its clinical studies [11]. Various other inhibitor molecules of this class are CP-358774, U0126, ZD1839 and BIBW2992 etc.

EGFR INHIBITORS: CLINICAL EVALUATIONS
Various EGFR inhibitors are undergoing clinical analysis and are exhibiting their remarkable results in the treatment of tumors and cancers. Erlotinib is under clinical studies phase III while Cetuximab is used for the treatment of patients suffering colorectal cancer. On other hand Gefitinib has shown efficient results in the treatment of lung cancer and NSCLC hence a very good radiographic and symptomatic response was observed in patients [11]. It was also used in vitro in the adinocarcinoma cell lines [12]. Erlotinib when induced in the patients of NSCLC in clinical studies of phase II, an improvement was observed in patient survival and the cancer associated symptoms [13]. The patients suffering NSCLC and are enrolled in the clinical trials phase I and phase II were administered with Bevacizumab and Erlotinib in combination (an anti- vascular endothelial growth factor monoclonal antibody), very good results were observed. A famous irreversible inhibitor of EGFR/HER2 is BIBW2992, when implied to the pre-clinical cancerous models showed efficacious results [15].

REFERENCES:
1. Lo HW, e.a., EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Research and Treatment, 2006.
2. Johnston JB, e.a., Targeting the EGFR Pathway for Cancer Therapy. Current Medicinal Chemistry, 2006.
3. Lo HW, e.a., Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. British Journal of Cancer, 2006.
4. Zelenaia O, e.a., Epidermal Growth Factor Receptor Agonists Increase Expression of Glutamate Transporter GLT-1 in Astrocytes through Pathways Dependent on Phosphatidylinositol 3-Kinase and Transcription Factor NF-κB Molecular Pharmacology, 2000.
5. Stamos J, e.a., Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem., 2002.
6. Kawamoto T, e.a., Quantitative Assay of Epidermal Growth Factor Receptor in Human Squamous Cell Carcinomas of the Oral Region by an Avidin-Biotin Method. Cancer Science, 1991.
7. Cappuzzo F, e.a., EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol, 2008.
8. Sharma AK, e.a., A dual immunocytochemical assay for oestrogen and epidermal growth factor receptors in tumour cell lines. The Histochemical Journal 1994.
9. Luca AD, e.a., Detection of Circulating Tumor Cells in Carcinoma Patients by a Novel Epidermal Growth Factor Receptor Reverse Transcription-PCR Assay. Clin Cancer Res, 2000.
10. Kumar RR, e.a., Enzyme immunoassay of human Epidermal Growth Factor Receptor (hEGFR). Human Antibodies, 2001.
11. Kris MG, e.a., Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients With Non-Small Cell Lung Cancer: A Randomized Trial. JAMA., 2003.
12. Paez JG, e.a., EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science, 2004.
13. Soler RP, e.a., Determinants of Tumor Response and Survival With Erlotinib in Patients With Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 2004.
14. Herbst RS, e.a., Phase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non-Small-Cell Lung Cancer Journal of Clinical Oncology, 2005.
15. Li D, e.a., BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene, 2008.

Cat.No.	Product Name	Information
S1023	Erlotinib HCl	Erlotinib HCl is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.
S1025	Gefitinib	Gefitinib 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. Gefitinib promotes autophagy and apoptosis of lung cancer cells via blockade of the PI3K/AKT/mTOR pathway.
S1102	U0126-EtOH	U0126-EtOH is a highly selective inhibitor of MEK1/2 with IC50 of 0.07 μM/0.06 μM in cell-free assays, 100-fold higher affinity for ΔN3-S218E/S222D MEK than PD98059. U0126 inhibits autophagy and mitophagy with antiviral activity.