Abstract
The receptor tyrosine kinase, c-Met and its ligand hepatocyte growth factor (HGF) are important regulators of malignancy in human cancer including brain tumors. c-Met is frequently activated in brain tumors and has emerged as a promising target for molecular therapies. Recently, an orally bioavailable small molecule kinase inhibitor of c-Met (SGX523) was developed by SGX Pharmaceuticals. We tested the effects of this inhibitor on c-Met brain tumor cell activation, c-Met-dependent malignancy, and in vivo glioma xenograft growth. SGX523 potently inhibited c-Met activation and c-Met-dependent signaling at nanomolar concentrations in glioma cells, primary gliomas, glioma stem cells and medulloblastoma cells. SGX523 treatment inhibited c-Met-dependent brain tumor cell proliferation and G1/S cell cycle progression. SGX523 also inhibited brain tumor cell migration and invasion. Furthermore, systemic delivery of SGX523 via oral gavage to mice bearing orthotopic human glioblastoma xenografts led to a significant decrease of in vivo tumor growth. These studies show that c-Met activation and c-Met-dependent brain tumor cell and stem cell malignancy can be inhibited by small molecules. The study also shows for the first time that oral delivery of a small molecule kinase inhibitor of c-Met inhibits intracranial tumor growth. These findings suggest that targeting c-Met with small molecule kinase inhibitors is a promising approach for brain tumor therapy.
Keywords: c-Met, glioblastoma, hepatocyte growth factor, kinase inhibitor, medulloblastoma, small molecule, scatter factor
Anti-Cancer Agents in Medicinal Chemistry
Title: An Orally Bioavailable c-Met Kinase Inhibitor Potently Inhibits Brain Tumor Malignancy and Growth
Volume: 10 Issue: 1
Author(s): Fadila Guessous, Ying Zhang, Charles diPierro, Lukasz Marcinkiewicz, Jann Sarkaria, David Schiff, Sean Buchanan and Roger Abounader
Affiliation:
Keywords: c-Met, glioblastoma, hepatocyte growth factor, kinase inhibitor, medulloblastoma, small molecule, scatter factor
Abstract: The receptor tyrosine kinase, c-Met and its ligand hepatocyte growth factor (HGF) are important regulators of malignancy in human cancer including brain tumors. c-Met is frequently activated in brain tumors and has emerged as a promising target for molecular therapies. Recently, an orally bioavailable small molecule kinase inhibitor of c-Met (SGX523) was developed by SGX Pharmaceuticals. We tested the effects of this inhibitor on c-Met brain tumor cell activation, c-Met-dependent malignancy, and in vivo glioma xenograft growth. SGX523 potently inhibited c-Met activation and c-Met-dependent signaling at nanomolar concentrations in glioma cells, primary gliomas, glioma stem cells and medulloblastoma cells. SGX523 treatment inhibited c-Met-dependent brain tumor cell proliferation and G1/S cell cycle progression. SGX523 also inhibited brain tumor cell migration and invasion. Furthermore, systemic delivery of SGX523 via oral gavage to mice bearing orthotopic human glioblastoma xenografts led to a significant decrease of in vivo tumor growth. These studies show that c-Met activation and c-Met-dependent brain tumor cell and stem cell malignancy can be inhibited by small molecules. The study also shows for the first time that oral delivery of a small molecule kinase inhibitor of c-Met inhibits intracranial tumor growth. These findings suggest that targeting c-Met with small molecule kinase inhibitors is a promising approach for brain tumor therapy.
Export Options
About this article
Cite this article as:
Guessous Fadila, Zhang Ying, diPierro Charles, Marcinkiewicz Lukasz, Sarkaria Jann, Schiff David, Buchanan Sean and Abounader Roger, An Orally Bioavailable c-Met Kinase Inhibitor Potently Inhibits Brain Tumor Malignancy and Growth, Anti-Cancer Agents in Medicinal Chemistry 2010; 10 (1) . https://dx.doi.org/10.2174/1871520611009010028
DOI https://dx.doi.org/10.2174/1871520611009010028 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
-
<i>Lophira alata</i> Suppresses Phorbol Ester-Mediated Increase in Cell Growth via Inhibition of Protein Kinase C-α/Akt in Glioblastoma Cells
Anti-Cancer Agents in Medicinal Chemistry Nanoparticle Coated Viral Vectors for Gene Therapy
Current Biotechnology Mesenchymal Stem Cells: Key Actors in Tumor Niche
Current Stem Cell Research & Therapy Chidamide Inhibits Cell Proliferation via the PI3K/AKT Pathway in K562 Cells Based on Network Pharmacology and Experimental Validation
Current Pharmaceutical Design MicroRNA-7 Regulates Insulin Signaling Pathway by Targeting IRS1, IRS2, and RAF1 Genes in Gestational Diabetes Mellitus
MicroRNA Lipid Nanocarriers for Neurotherapeutics: Introduction, Challenges, Blood-brain Barrier, and Promises of Delivery Approaches
CNS & Neurological Disorders - Drug Targets The Applicability of mTOR Inhibition in Solid Tumors
Current Cancer Drug Targets Glioma Stem Cell Maintenance: The Role of the Microenvironment
Current Pharmaceutical Design Targeting Role of Glioma Stem Cells for Glioblastoma Multiforme
Current Medicinal Chemistry KIAA0101 in Malignant Pleural Mesothelioma: A Potential Diagnostic and Prognostic Marker
Combinatorial Chemistry & High Throughput Screening Current Insights into the Role of HIF-1 in Cutaneous Wound Healing
Current Molecular Medicine Vascular Endothelial Growth Factor as an Anti-Angiogenic Target for Cancer Therapy
Current Drug Targets Circumventing Melanoma Chemoresistance by Targeting DNA Repair
Current Medicinal Chemistry Sphingosine Kinases Signalling in Carcinogenesis
Mini-Reviews in Medicinal Chemistry Synthesis and Evaluation of Heterocycles Based Chalcone Derivatives as Antiproliferative Agents
Anti-Cancer Agents in Medicinal Chemistry Age and Dose-Dependent Effects of Alpha-Lipoic Acid on Human Microtubule- Associated Protein Tau-Induced Endoplasmic Reticulum Unfolded Protein Response: Implications for Alzheimer’s Disease
CNS & Neurological Disorders - Drug Targets Imaging of Hypoxia Using PET and MRI
Current Pharmaceutical Biotechnology Circulating microRNAs in Hepatocellular Carcinoma: Potential Diagnostic and Prognostic Biomarkers
Current Pharmaceutical Design The Role of Emerging Genomics and Proteomics Technologies in Cancer Drug Target Discovery
Current Cancer Drug Targets Molecular Response to Hypericin-Induced Photodamage
Current Medicinal Chemistry