EGFR INHIBITORS AGAINST TUMORS

by Selleckchem | Jul 29 2012

EGFR INHIBITION:
There are few pathways which play important roles in the cellular functioning and among these EGFR (epidermal growth factor receptor) pathway is one which is vital for the cell growth, proliferation and survival. The significance of this pathway can only be understood by the formation of cancers and fatal diseases associated with uncontrolled growth of cells due to dysregulation of EGFR signaling pathway. Mutated or over expression of EGFR is linked with many types of cancers for example breast, colon and lung cancers [1] and also with glioblastoma multiform, epithelial and anal cancers. Therefore an attractive strategy to treat cancers was EGFR inhibition by using EGFR inhibitors [2]. In addition to this use in clinics these are also involved in patient survival [3] and various EGFR agonists and antagonists are also being used for the elucidation of different other pathways and effects of EGFR signaling pathway on them [4]. These inhibitors are available at normal prices from any of the relevant supplier.

DIFFERENT EGFR INHIBITORS AND THEIR MODE OF ACTION:
Different EGFR inhibitors have been discovered by novel techniques such as high throughput chemical screening and have potent activities. The discovery and detailed knowledge about EGFR crystal structure also enhanced the use of various EGFR inhibitors [5]. For the assessment of efficacy of certain inhibitor one can use different assays such as avidin biotin assay for quantitative assay [6], FISH or fluorescent in situ hybridization [7], dual immmunocytochemical assays [8], Real time PCR [9] and also enzyme immunoassays [10] and these assays are mostly done prior and after the use of inhibitor. One of the most renowned specific inhibitor of EGFR is Erlotinib as its structure contains 4-anilinoquinazoline which specifies EGFR target [5]. Gefitinib has also gained a remarkable success after its clinical trials [11]. And many other inhibitors of this category are BIBW2992, CP-358774, ZD1839 and U0126 etc.

EGFR INHIBITORS IN CLINICAL EVALUATIONS:
There are various EGFR inhibitors which are undergoing clinical trials are showing their excellent results in treating cancers and tumors. Erlotinib is in clinical trials phase III whereas Cetuximab is administered to patients having colorectal cancers. Gefitinib on the other hand have shown remarkable results in the treatment of NSCLC and lung cancer where good symptomatic and radiographic response was seen in patient [11] as it was used before in vitro in cell lines of adenocarcinoma [12]. In NSCLC patients when Erlotinib was administered during phase II of clinical studies, improvements in cancer related symptoms and patients survival rate [13]. Patients having NSCLC and enrolled in phase I and II of clinical studies when co administered with Erlotinib and Bevacizumab that is a monoclonal antibody against VEGF (vascular endothelial growth factor) good results were noted. BIBW2992 that is a EGFR/HER2 irreversible inhibitor when applied to preclinical models of cancers it showed efficient 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
S1011	Afatinib	Afatinib inhibits EGFR/ErbB irreversibly in vitro with IC50 of 0.5, 0.4, 10, 14, 1 nM for EGFR^wt, EGFR^L858R, EGFR^L858R/T790M ErbB2 (HER2) and ErbB4 (HER4), respectively. Afatinib induces autophagy.
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.