Abstract
Increasing knowledge of the structure and function of the Epidermal Growth Factor Receptor (EGFR) subfamily of tyrosine kinases, and of their role in the initiation and progression of various cancers has led to the search for inhibitors of signaling molecules that may prove to be important in cancer therapy. The complex nature of EGFR biology allows for potential opportunities for EGFR inhibitors in a number of areas of cancer therapy, including proliferative, angiogenic, invasive, and metastatic aspects. Different approaches have been used to target either the extracellular ligand-binding domain of the EGFR or the intracellular tyrosine kinase region that results in interference with its signaling pathways that modulate cancer-promoting responses. Examples of these include a number of monoclonal antibodies, immunotoxins and ligand-binding cytotoxic agents that target the extracellular ligand binding region of EGFR, and small molecule inhibitors that target the intracellular kinase domain and act by interfering with ATP binding to the receptor. During the past 3 years, significant progress has been made towards the identification of new structural classes of small molecule inhibitors that show high potency and specificity towards EGFR. The search for new small molecules that inhibit kinases has included traditional approaches like the testing of natural products, random screening of chemical libraries, the use of classical structure-activity-relationship studies, and the incorporation of structurebased drug design and combinatorial chemistry techniques. There has been a significant improvement in the development of selective EGFR inhibitors with the use of a structure-based design approach employing a homology model of the EGFR kinase domain. Molecular modeling procedures have been used to generate novel molecules that are complementary in shape and electrostatics to the EGFR kinase domain topography. This review focuses on some examples of the successful use of this method.
Current Cancer Drug Targets
Title: Rational Design of Potent and Selective EGFR Tyrosine Kinase Inhibitors as Anticancer Agents
Volume: 1 Issue: 2
Author(s): Sutapa Ghosh, Xing-Ping Liu, Yaguo Zheng and Fatih M. Uckun
Affiliation:
Abstract: Increasing knowledge of the structure and function of the Epidermal Growth Factor Receptor (EGFR) subfamily of tyrosine kinases, and of their role in the initiation and progression of various cancers has led to the search for inhibitors of signaling molecules that may prove to be important in cancer therapy. The complex nature of EGFR biology allows for potential opportunities for EGFR inhibitors in a number of areas of cancer therapy, including proliferative, angiogenic, invasive, and metastatic aspects. Different approaches have been used to target either the extracellular ligand-binding domain of the EGFR or the intracellular tyrosine kinase region that results in interference with its signaling pathways that modulate cancer-promoting responses. Examples of these include a number of monoclonal antibodies, immunotoxins and ligand-binding cytotoxic agents that target the extracellular ligand binding region of EGFR, and small molecule inhibitors that target the intracellular kinase domain and act by interfering with ATP binding to the receptor. During the past 3 years, significant progress has been made towards the identification of new structural classes of small molecule inhibitors that show high potency and specificity towards EGFR. The search for new small molecules that inhibit kinases has included traditional approaches like the testing of natural products, random screening of chemical libraries, the use of classical structure-activity-relationship studies, and the incorporation of structurebased drug design and combinatorial chemistry techniques. There has been a significant improvement in the development of selective EGFR inhibitors with the use of a structure-based design approach employing a homology model of the EGFR kinase domain. Molecular modeling procedures have been used to generate novel molecules that are complementary in shape and electrostatics to the EGFR kinase domain topography. This review focuses on some examples of the successful use of this method.
Export Options
About this article
Cite this article as:
Ghosh Sutapa, Liu Xing-Ping, Zheng Yaguo and Uckun M. Fatih, Rational Design of Potent and Selective EGFR Tyrosine Kinase Inhibitors as Anticancer Agents, Current Cancer Drug Targets 2001; 1 (2) . https://dx.doi.org/10.2174/1568009013334188
DOI https://dx.doi.org/10.2174/1568009013334188 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
The Effects of Psychological Stress on Depression
Current Neuropharmacology Conserved Regions can Predict Protein Binding Regions
Current Proteomics Meet Our Editorial Board Member
Current Cancer Drug Targets Overview of SLC22A and SLCO Families of Drug Uptake Transporters in the Context of Cancer Treatments
Current Drug Metabolism Meet Our Editorial Board Member:
Current Pharmaceutical Design Astrocytes as a 5-HT2B-Mediated SERT-Independent SSRI Target, Slowly Altering Depression-Associated Genes and Function
Current Signal Transduction Therapy Inhibition of Polo-Like Kinase 1 by BI2536 Reverses the Multidrug Resistance of Human Hepatoma Cells In Vitro and In Vivo
Anti-Cancer Agents in Medicinal Chemistry Recent Developments of Melatonin Related Antioxidant Compounds
Combinatorial Chemistry & High Throughput Screening Cutting the Limits of Aminobisphosphonates: New Strategies for the Potentiation of their Anti-Tumour Effects
Current Cancer Drug Targets Hyaluronate-Lipid Nanohybrids: Fruitful Harmony in Cancer Targeting
Current Pharmaceutical Design Synthesis and Hypoxia Selective Radiosensitization Potential of β-2-FAZA and β-3-FAZL: Fluorinated Azomycin β-Nucleosides
Medicinal Chemistry Chemistry and Pharmacological Properties of Some Natural and Synthetic Antioxidants for Heavy Metal Toxicity
Current Medicinal Chemistry Modelling and Dosimetry for Alpha-Particle Therapy
Current Radiopharmaceuticals Resistance to Chemotherapy and Molecularly Targeted Therapies: Rationale for Combination Therapy in Malignant Melanoma
Current Molecular Medicine Fc Engineering to Improve the Function of Therapeutic Antibodies
Current Pharmaceutical Biotechnology Doxorubicin-Loaded Micelle Targeting MUC1: A Potential Therapeutic for MUC1 Triple Negative Breast Cancer Treatment
Current Drug Delivery The Importance of Lamivudine Therapy in Liver Cirrhosis Patients Related HBV with Advanced Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy
Clinical Cancer Drugs Intraperitoneal Chemotherapy as Primary Treatment of Advanced Ovarian Cancer:Efficacy, Toxicity, and Future Directions
Reviews on Recent Clinical Trials Multifunctional Materials for Cancer Therapy: From Antitumoral Agents to Innovative Administration
Current Organic Chemistry Dysfunctional Mechanism of Liver Cancer Mediated by Transcription Factor and Non-coding RNA
Current Bioinformatics