Abstract
The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/ Herceptin™ and cetuximab/Erbitux™ ) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa™ and erlotinib/Tarceva™). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb™), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.
Keywords: Antitumour, bioisostere, EGFR, erlotinib, gefitinib, HER-2, tyrosine kinase inhibitor, quinazoline, type I receptor tyrosine kinases, ErbB receptors, simultaneous targeting
Current Medicinal Chemistry
Title: Novel Substituted Quinazolines for Potent EGFR Tyrosine Kinase Inhibitors
Volume: 18 Issue: 7
Author(s): O. Cruz-Lopez, A. Conejo-Garcia, M. C. Nunez, M. Kimatrai, M. E. Garcia-Rubino, F. Morales, V. Gomez-Perez and J. M. Campos
Affiliation:
Keywords: Antitumour, bioisostere, EGFR, erlotinib, gefitinib, HER-2, tyrosine kinase inhibitor, quinazoline, type I receptor tyrosine kinases, ErbB receptors, simultaneous targeting
Abstract: The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/ Herceptin™ and cetuximab/Erbitux™ ) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa™ and erlotinib/Tarceva™). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb™), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.
Export Options
About this article
Cite this article as:
Cruz-Lopez O., Conejo-Garcia A., C. Nunez M., Kimatrai M., E. Garcia-Rubino M., Morales F., Gomez-Perez V. and M. Campos J., Novel Substituted Quinazolines for Potent EGFR Tyrosine Kinase Inhibitors, Current Medicinal Chemistry 2011; 18 (7) . https://dx.doi.org/10.2174/092986711794940824
DOI https://dx.doi.org/10.2174/092986711794940824 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
- Announcements
Related Articles
-
The Role of Phospholipase D Enzyme(s) in Modulating Cell Signaling: Implications for Cancer Drug Development
Current Bioactive Compounds Autophagy as a Potential Therapeutic Target in Breast Cancer Treatment
Current Cancer Drug Targets Post-Transcriptional and Post-translational Regulation of Central Carbon Metabolic Enzymes in Cancer
Anti-Cancer Agents in Medicinal Chemistry Contrast Agents in X-Ray Computed Tomography and Its Applications in Oncology
Anti-Cancer Agents in Medicinal Chemistry Dimeric Approaches to Anti-Cancer Chemotherapeutics
Anti-Cancer Agents in Medicinal Chemistry Carbohydrate Antigens: Synthesis Aspects and Immunological Applications in Cancer
Mini-Reviews in Medicinal Chemistry Onco-Surgical Management of Colo-Rectal Liver Metastases in Older Patients: A New Frontier in the 3<sup>rd</sup> Millennium
Anti-Cancer Agents in Medicinal Chemistry Enrichment of Up-regulated and Down-regulated Gene Clusters Using Gene Ontology, miRNAs and lncRNAs in Colorectal Cancer
Combinatorial Chemistry & High Throughput Screening Recent Development of CB2 Selective and Peripheral CB1/CB2 Cannabinoid Receptor Ligands
Current Medicinal Chemistry The Ultrasonographic Diagnosis of Polycystic Ovary Syndrome
Current Medical Imaging Changes of Gene Expression in the Developing Brain by Acute Ethanol Exposure
Current Psychopharmacology Cytotoxic and Chemopreventive Effects of Gemin D Against Different Mutagens Using In Vitro and In Vivo Assays
Anti-Cancer Agents in Medicinal Chemistry Oxidative Stress and Cancer: The Role of Nrf2
Current Cancer Drug Targets Anti Tumor Necrosis Factor Alpha (TNFα) Therapy in Ankylosing Spondylitis - Asian Perspective
Current Rheumatology Reviews Recent Advances in Optical Mammography
Current Medical Imaging Targeting Trail Towards the Clinic
Current Drug Targets Radiopharmaceutical Applications of Organometallic Technetium and Rhenium Complexes
Current Inorganic Chemistry (Discontinued) Phytoestrogens and Mitochondrial Biogenesis in Breast Cancer. Influence of Estrogen Receptors Ratio
Current Pharmaceutical Design Recent Progress in the Development of Quinoline Derivatives for the Exploitation of Anti-Cancer Agents
Anti-Cancer Agents in Medicinal Chemistry Potential Application of Biliverdin Reductase and its Fragments to Modulate insulin/IGF-1/MAPK/PI3-K Signaling Pathways in Therapeutic Settings
Current Drug Targets