Abstract
Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC50 of 0.04 μM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.
Keywords: FGFR4, inhibitor, phosphorylation, tyrosine kinase
Current Medicinal Chemistry
Title:Developing FGFR4 Inhibitors As Potential Anti-Cancer Agents Via In Silico Design, Supported by In Vitro and Cell-Based Testing
Volume: 20 Issue: 10
Author(s): Z. Horvath, B. T. Chua, G. Keri, A. Ullrich, L. Orfi, F. Baska, B. Szokol, I. Szabadkai, J. Pato, H. K. Ho, Z. Greff, N. Breza, L. Zsakai, C. Szantai-Kis, E. Pang, Y. R. Ng and G. Nemeth
Affiliation:
Keywords: FGFR4, inhibitor, phosphorylation, tyrosine kinase
Abstract: Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC50 of 0.04 μM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.
Export Options
About this article
Cite this article as:
Horvath Z., T. Chua B., Keri G., Ullrich A., Orfi L., Baska F., Szokol B., Szabadkai I., Pato J., K. Ho H., Greff Z., Breza N., Zsakai L., Szantai-Kis C., Pang E., R. Ng Y. and Nemeth G., Developing FGFR4 Inhibitors As Potential Anti-Cancer Agents Via In Silico Design, Supported by In Vitro and Cell-Based Testing, Current Medicinal Chemistry 2013; 20 (10) . https://dx.doi.org/10.2174/0929867311320100001
DOI https://dx.doi.org/10.2174/0929867311320100001 |
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
-
Role of Flavonoids in Future Anticancer Therapy by Eliminating the Cancer Stem Cells
Current Stem Cell Research & Therapy Parathyroid Hormone Determination in Ultrasound-Guided Fine Needle Aspirates Allows the Differentiation between Thyroid and Parathyroid Lesions: Our Experience and Review of the Literature
Endocrine, Metabolic & Immune Disorders - Drug Targets The Yin and Yang of Non-Neuronal α7-Nicotinic Receptors in Inflammation and Autoimmunity
Current Drug Targets Role of PARP Inhibitors in Cancer Biology and Therapy
Current Medicinal Chemistry Arginyl Aminopeptidase-Like 1 (RNPEPL1) Is an Alternatively Processed Aminopeptidase with Specificity for Methionine, Glutamine, and Citrulline Residues
Protein & Peptide Letters Dimeric Approaches to Anti-Cancer Chemotherapeutics
Anti-Cancer Agents in Medicinal Chemistry LncRNA HOTAIR as Prognostic Circulating Marker and Potential Therapeutic Target in Patients with Tumor Diseases
Current Drug Targets Mast Cells as Target in Cancer Therapy
Current Pharmaceutical Design PI3K/AKT/mTOR Inhibitors In Ovarian Cancer
Current Medicinal Chemistry Ellagic Acid Enhances the Efficacy of PI3K Inhibitor GDC-0941 in Breast Cancer Cells
Current Molecular Medicine Recent Developments in the Chemical Biology of Epothilones
Current Pharmaceutical Design Molecular Imaging of Apoptosis with Radio-Labeled Annexin A5 Focused on the Evaluation of Tumor Response to Chemotherapy
Anti-Cancer Agents in Medicinal Chemistry Membrane Targeted Chemotherapy with Hybrid Liposomes for Tumor Cells Leading to Apoptosis
Current Pharmaceutical Design New Prospects for Nelfinavir in Non-HIV-Related Diseases
Current Molecular Pharmacology Epigenetic Regulation of Genes Encoding Drug-Metabolizing Enzymes and Transporters; DNA Methylation and Other Mechanisms
Current Drug Metabolism Inducing Tumor Cell Apoptosis: Mediated Survivin miRNA by Ultrasound and Cationic Lipid Contrast Agent
Current Molecular Medicine The Screening of Renoprotective Agents by 99mTc-DMSA: A Review of Preclinical Studies
Current Radiopharmaceuticals Indoleamine 2,3-Dioxygenase, an Emerging Target for Anti-Cancer Therapy
Current Cancer Drug Targets Patent Selections
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Nanomedicine for Gene Delivery for the Treatment of Cardiovascular Diseases
Current Gene Therapy