Abstract
The discovery of hypoxia-inducible factor-1 has led to a rapidly increasing understanding of the molecular mechanism of tumor hypoxia in the past two decades. Today it is generally accepted that HIF-1 plays a pivotal role in the cellular response to tumor hypoxia which represents a major obstacle to the success of radiotherapy and chemotherapy. Meanwhile, many details involved in the expression, accumulation and transactivation of HIF-1 have been well elucidated. Targeting HIF-1 has become a novel and efficient strategy for cancer therapy and a number of agents have been developed aiming to suppress HIF-1. This review will concisely introduce the general knowledge on the molecular biology of HIF-1 and possible targets along the HIF-1 pathway. Moreover, a number of compounds reported with anti-HIF-1 activity are included and mainly classified as direct and indirect inhibitors based on their different modes of action. While direct HIF-1 inhibitors prevent HIF-1 from transactivation, DNA binding and subsequently initiating transcriptional activity, indirect HIF-1 inhibitors generally block the transcription or translation of HIF-1α or promote the degradation of HIF-1α protein. According to different structural features, direct HIF-1 inhibitors are divided into several groups: polyamides, quinols and naphthoquinone spiroketal analogues, shikonin derivatives, epidithiodiketopiperazines, and two representative drugs: echinomycin and bortezomib. In the same way, indirect inhibitors comprise the following classes: polyphenols, benzoazaheterocycles, rapamycins, camptothecins, geldanamycins, (aryloxyacetylamino)benzoic acid analogues, 2-methoxyestradiol and analogues, hydroxamic acid compounds and others. The rest with mechanism still not so clear would also be listed and introduced, with an emphasis on the marinederived natural products. The in vitro and/or in vivo activities of these compounds and their mechanisms of HIF-1 inhibition would be discussed and the SARs of unique structural types of HIF-1 inhibitors will be briefly concluded.
Keywords: Camptothecins, direct inhibitors, geldanamycins, HIF-1 inhibitors, hypoxia, hypoxia-inducible factor-1, indirect inhibitors, mechanism, 2-methoxyestradiol, polyamides, polyphenols, rapamycins, SARs, shikonin derivatives
Current Medicinal Chemistry
Title: Cancer Therapeutic Agents Targeting Hypoxia-Inducible Factor-1
Volume: 18 Issue: 21
Author(s): R. Wang, S. Zhou and S. Li
Affiliation:
Keywords: Camptothecins, direct inhibitors, geldanamycins, HIF-1 inhibitors, hypoxia, hypoxia-inducible factor-1, indirect inhibitors, mechanism, 2-methoxyestradiol, polyamides, polyphenols, rapamycins, SARs, shikonin derivatives
Abstract: The discovery of hypoxia-inducible factor-1 has led to a rapidly increasing understanding of the molecular mechanism of tumor hypoxia in the past two decades. Today it is generally accepted that HIF-1 plays a pivotal role in the cellular response to tumor hypoxia which represents a major obstacle to the success of radiotherapy and chemotherapy. Meanwhile, many details involved in the expression, accumulation and transactivation of HIF-1 have been well elucidated. Targeting HIF-1 has become a novel and efficient strategy for cancer therapy and a number of agents have been developed aiming to suppress HIF-1. This review will concisely introduce the general knowledge on the molecular biology of HIF-1 and possible targets along the HIF-1 pathway. Moreover, a number of compounds reported with anti-HIF-1 activity are included and mainly classified as direct and indirect inhibitors based on their different modes of action. While direct HIF-1 inhibitors prevent HIF-1 from transactivation, DNA binding and subsequently initiating transcriptional activity, indirect HIF-1 inhibitors generally block the transcription or translation of HIF-1α or promote the degradation of HIF-1α protein. According to different structural features, direct HIF-1 inhibitors are divided into several groups: polyamides, quinols and naphthoquinone spiroketal analogues, shikonin derivatives, epidithiodiketopiperazines, and two representative drugs: echinomycin and bortezomib. In the same way, indirect inhibitors comprise the following classes: polyphenols, benzoazaheterocycles, rapamycins, camptothecins, geldanamycins, (aryloxyacetylamino)benzoic acid analogues, 2-methoxyestradiol and analogues, hydroxamic acid compounds and others. The rest with mechanism still not so clear would also be listed and introduced, with an emphasis on the marinederived natural products. The in vitro and/or in vivo activities of these compounds and their mechanisms of HIF-1 inhibition would be discussed and the SARs of unique structural types of HIF-1 inhibitors will be briefly concluded.
Export Options
About this article
Cite this article as:
Wang R., Zhou S. and Li S., Cancer Therapeutic Agents Targeting Hypoxia-Inducible Factor-1, Current Medicinal Chemistry 2011; 18 (21) . https://dx.doi.org/10.2174/092986711796391606
DOI https://dx.doi.org/10.2174/092986711796391606 |
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
-
Editorial (Thematic Issue: Natural Products in Cancer Prevention and Therapy, a selection of topics presented in the 2nd Edition PSE Symposium (Naples, Italy, 25th to 28th of June 2013))
Anti-Cancer Agents in Medicinal Chemistry 2D, 3D, G-QSAR and Docking Studies of Thiazolyl-pyrazoline Analogues as Potent (Epidermal Growth Factor Receptor-tyrosine Kinase) EGFR-TK Inhibitors
Letters in Drug Design & Discovery The Interaction of Histone Deacetylase Inhibitors and DNA Methyltransferase Inhibitors in the Treatment of Human Cancer Cells
Current Medicinal Chemistry - Anti-Cancer Agents Targeting of Low-Molecular Weight Drugs to Mammalian Mitochondria
Drug Design Reviews - Online (Discontinued) Meet Our Section Editor
Current Cancer Drug Targets Anti-Epidermal Growth Factor Receptor Antibodies in the Treatment of Metastatic Colorectal Cancer
Recent Patents on Anti-Cancer Drug Discovery Green Reduction of Graphene Oxide into Graphene by Cow Urine
Current Nanomaterials Treatment for Radiation-Induced Pulmonary Late Effects: Spoiled for Choice or Looking in the Wrong Direction?
Current Drug Targets The Epithelial-Mesenchymal Transition and Cancer Stem Cells: Functional and Mechanistic Links
Current Pharmaceutical Design Jun Dimerization Protein 2: A Multifunctional Transcription Factor in Mammalian Cells
Current Genomics Accessing Targeted Nanoparticles to the Brain: The Vascular Route
Current Medicinal Chemistry Comparative Binding Mode and Residual Contribution from Lactoferrins (bLF and hLF) and HIV Gp120: An In silico Structural Perspective to Design Potent Peptide Inhibitor for HIV
Current Enzyme Inhibition Microtubule Targeting Agents: A Benchmark in Cancer Therapy
Current Drug Therapy Drug Combinations Enhancing the Antineoplastic Effects of Erlotinib in High-Grade Glioma
Recent Patents on Anti-Cancer Drug Discovery Pharmacophore Based 3D-QSAR Study of Biphenyl Derivatives as Nonsteroidal Aromatase Inhibitors in JEG-3 Cell Lines
Medicinal Chemistry Stem Cell Ageing and Apoptosis
Current Pharmaceutical Design Cytochrome P450-based Gene Therapy for Cancer Treatment: From Concept to the Clinic
Current Drug Metabolism Prospects for Clinical Introduction of Nitroimidazole Antibiotics for the Treatment of Tuberculosis
Current Pharmaceutical Design Serum MicroRNA-21 as a Biomarker for Allergic Inflammatory Disease in Children
MicroRNA Inhibitors of Bacterial Efflux Pumps as Adjuvants in Antibiotic Treatments and Diagnostic Tools for Detection of Resistance by Efflux
Recent Patents on Anti-Infective Drug Discovery