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Introduction High throughput screening is a wonder tool to identify the targets like needles in the haystack. This technique has been able to provide screening libraries which inhibit a wide range of targets having a heady role in a variety of leukemias. The inhibitors provided in compound libraries can hijack various crucial points in signaling pathways which otherwise lead to cancer. HTS inhibitors find their target sites in receptors like COX-2, PARP, GPCRs, Tyrosine kinases etc. Most of the inhibitors in HTS libraries have found their pragmatic applications in clinical pharmacology and are being used as medical drugs for cancer. EGFR are one of those receptors, which have reported to be involved in cancer, find their best inhibitors by HTS. Role of EGF Receptors When a ligand binds the monomeric ligand binding site of EGF receptors, the receptor dimerizes with the subsequent auto-phosphorylation of the intracellular domains of the receptors. The phosphorylation activates the downstream signaling pathways which trigger various cellular processes like proliferation, survival, adhesion etc. Link of EGF Receptors to Cancer Numerous genetic and epigenetic factors cause cancerous mutations in the EGF receptors. Most of these mutations lead to over-activation of the receptors which results in cancerous proliferation of cells and metastasis. The EGF receptor mutations have been linked to multicentric adenocarcinoma, bronchioloalveolar carcinoma, atypical adenomatous hyperplasia, breast cancer and lung cancer. ”" Inhibitors for EGF Receptors Adverse effects of EGFR mutations can be decreased by targeting these receptors with appropriate inhibitors. There are two important sites in receptors against which egfr inhibitors can be designed as shown in the figure [1]. 1. The ligand-binding site: Monoclonal antibodies like Erbitux bind the EGFR at the ligand-binding sites. Such antibodies block the receptor from responding to extracellular signals which inhibits the activation of downstream signaling pathways. 2. Auto-phosphorylation Site: The second potent target site is the auto-phosphorylation site present on the inner side of membrane. Drugs like Iressa (Gefitinib) and Erlotinib have been the successful inhibitor in this case. They block the EGFR kinases so that they cannot add phosphate groups thus preventing the auto-phosphorylation. Combination of two Target Inhibitors It can be proposed that the combined use of ligand binding site inhibitors and auto-phosphorylation preventing inhibitors will prove to be useful in impeding the rate of metastasis. Research has proved this proposition to be highly effective in the treatment of cancer. EGF receptors are more effectively inhibited if both types of inhibitors are used in live cells assays as well as in human beings [2]. A Drawback Recent studies report that Iressa has been linked to deaths in some countries like Japan. This drug was approved by FDA, but unfortunately with the increasing rates of mutations in human genome, this drug is losing its effectiveness on clinical trials. Nowadays, erlotinib is more recommended as compared to Iressa for inhibiting EGF receptor tyrosine kinases [3]. Conclusion Failure of gefitinib potentiates the use of virtual screens and high throughput screening technologies to design better models for EGFR inhibitors. Virtual screenings provide useful insight into the chemical structure of targets and the possible binding mechanism of designed inhibitors. These may be used to decrease the toxicity levels of the drugs and to increase their solubility. Leads can be collected by HTS assays and optimized on clinical trials. HTS is a technology which calls for its users for incessant colossal work which can be done to transfigure the medical literature and drug industry! References 1. Cheng L, Zhang S, et al. Landscape of EGFR Pathways and Personalized Management of NSCLC: EGFR Pathway Alteration & Implications. Future Oncology 2011; 7(4):519-541. 2. Frantz S. Iressa failure fears aout accelerated approvals. Nature Reviews Drug Discovery 2005; 4(94). 3. American Association for Cancer Research. Two-pronged Attack Targeting EGF Receptor Hinders Cancer Cell Growth. Sciencedaily 2004. Web. 16 Dec. 2011. Related Posts Fostamatinib: A Potent Inhibitor of Spleen Tyrosine Kinase HDAC: A Beneficial Target for HTS Related to EGF Receptor: An Expedient Target for HTS Dasatinib: A better inhibitor than Imatinib Introduction The slant of inhibitors, used in laboratories for screening analysis and health centers as drugs, is mounting fast with time. Nevertheless, one of the ... The Difference between HTS and HCS HTS and HCS are two colors of screening tests’ rainbow whose boundaries are quite diffused. Both are high quality, remarkably significant, and exceptionally dependable tools ... HTS and Drug Discovery A man of Stone Age if brought into the contemporary world will not deem in the innovations made so far even after visualizing them. But ... As one of the world leading suppliers of high-performance life-science products. We have over 8,000 products which consist of inhibitors, antibodies, RNAis, proteins and peptides those which focus on signaling pathways such as cdk inhibitors, egfr inhibitor, egfr inhibitors & so on. Furthermore, compound libraries for high-throughput screening and high-content screening are also available.
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