Abstract
The carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX and XII are predominantly found in tumor cells and show a restricted expression in normal tissues. By efficiently hydrating carbon dioxide to protons and bicarbonate, these CAs contribute significantly to the extracellular acidification of solid tumors. CA IX and XII are overexpressed in many such tumors in response to the hypoxia inducible factor (HIF) pathway, and research on the involvement of these isozymes in cancer has progressed in recent years. The report of the X-ray crystal structure of CA IX, which is a dimeric protein with a quaternary structure not evidenced earlier for this family of enzymes, allows for structure-based drug design campaigns of inhibitors against this novel antitumor target. Indeed, it has been known for some time that aromatic/ heterocyclic sulfonamides and sulfamates have good affinity for this isoform, but generally they do not show specificity for the inhibition of the tumor-associated isoform versus the remaining CA isozymes (CA I-VII, and XII-XV) found in mammals. Recently, we reported several classes of compounds with good selectivity for the tumor-associated CAs, being shown that CA IX/XII inhibition reverses the effect of tumor acidification, leading to inhibition of the cancer cells growth. CA IX/XII are now proposed as novel therapeutic antitumor targets. Furthermore, as some types of CA inhibitors (CAIs), such as the fluorescent sulfonamides accumulate only in hypoxic tumor cells overexpressing these enzymes, CAIs may be also used as diagnostic tools for imaging of hypoxic cancer cells. Work from several laboratories recently reported the proof-of-concept studies for the use of CA IX/XII inhibitors as well as antibodies both in the therapy and imaging of hypoxic tumors.
Keywords: Carbonic anhydrase (CA), CA IX, CA XII, hypoxia, sulfonamides, enzyme selective inhibition, tumorigenesis, tumor imaging, tumor acidification, X-ray crystallography, phenol, coumarin, antibody
Current Medicinal Chemistry
Title: Drug Design Studies of the Novel Antitumor Targets Carbonic Anhydrase IX and XII
Volume: 17 Issue: 15
Author(s): O. Ozensoy Guler, G. De Simone and C. T. Supuran
Affiliation:
Keywords: Carbonic anhydrase (CA), CA IX, CA XII, hypoxia, sulfonamides, enzyme selective inhibition, tumorigenesis, tumor imaging, tumor acidification, X-ray crystallography, phenol, coumarin, antibody
Abstract: The carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX and XII are predominantly found in tumor cells and show a restricted expression in normal tissues. By efficiently hydrating carbon dioxide to protons and bicarbonate, these CAs contribute significantly to the extracellular acidification of solid tumors. CA IX and XII are overexpressed in many such tumors in response to the hypoxia inducible factor (HIF) pathway, and research on the involvement of these isozymes in cancer has progressed in recent years. The report of the X-ray crystal structure of CA IX, which is a dimeric protein with a quaternary structure not evidenced earlier for this family of enzymes, allows for structure-based drug design campaigns of inhibitors against this novel antitumor target. Indeed, it has been known for some time that aromatic/ heterocyclic sulfonamides and sulfamates have good affinity for this isoform, but generally they do not show specificity for the inhibition of the tumor-associated isoform versus the remaining CA isozymes (CA I-VII, and XII-XV) found in mammals. Recently, we reported several classes of compounds with good selectivity for the tumor-associated CAs, being shown that CA IX/XII inhibition reverses the effect of tumor acidification, leading to inhibition of the cancer cells growth. CA IX/XII are now proposed as novel therapeutic antitumor targets. Furthermore, as some types of CA inhibitors (CAIs), such as the fluorescent sulfonamides accumulate only in hypoxic tumor cells overexpressing these enzymes, CAIs may be also used as diagnostic tools for imaging of hypoxic cancer cells. Work from several laboratories recently reported the proof-of-concept studies for the use of CA IX/XII inhibitors as well as antibodies both in the therapy and imaging of hypoxic tumors.
Export Options
About this article
Cite this article as:
Guler Ozensoy O., Simone De G. and Supuran T. C., Drug Design Studies of the Novel Antitumor Targets Carbonic Anhydrase IX and XII, Current Medicinal Chemistry 2010; 17 (15) . https://dx.doi.org/10.2174/092986710790979999
DOI https://dx.doi.org/10.2174/092986710790979999 |
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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Second Generation Adeno-Associated Virus Type 2-based Gene Therapy Systems with the Potential for Preferential Integration into AAVS1
Current Gene Therapy Exploring the Role of Phytochemicals as Potent Natural Photosensitizers in Photodynamic Therapy
Anti-Cancer Agents in Medicinal Chemistry Cytotoxic, Apoptotic and DNA Synthesis Inhibitory Effects of Some Thiazole Derivatives
Letters in Drug Design & Discovery Potential Uses of MicroRNA in Lung Cancer Diagnosis, Prognosis, and Therapy
Current Cancer Drug Targets Hypoxia Selects for a Quiescent, CML Stem/Leukemia Initiating- Like Population Dependent on CBP/Catenin Transcription
Current Molecular Pharmacology Future Prospects for Targeted Alpha Therapy
Current Radiopharmaceuticals Targeting the JAK/STAT Signaling Pathway for Breast Cancer
Current Medicinal Chemistry Novel Marine-Derived Anti-Cancer Agents
Current Pharmaceutical Design Nanomedicines Based Drug Delivery Systems for Anti-Cancer Targeting and Treatment
Current Drug Delivery A Closer Look at α-Secretase
Current Alzheimer Research Overcoming the Blood-Brain Barrier for Chemotherapy: Limitations, Challenges and Rising Problems
Anti-Cancer Agents in Medicinal Chemistry Pharmacological Modulation of Nitric Oxide Release: New Pharmacological Perspectives, Potential Benefits and Risks
Current Medicinal Chemistry Antiangiogenic Therapy for High-Grade Gliomas
CNS & Neurological Disorders - Drug Targets Cellular Photodynamic Toxicity of Hematoporphyrin in Various Nanocarrier Systems
Current Nanoscience Lipid-Based Vectors for Therapeutic mRNA-Based Anti-Cancer Vaccines
Current Pharmaceutical Design Prevention of Intracerebral Haemorrhage
Current Drug Targets Neurodegenerative Diseases of the Retina and Potential for Protection and Recovery
Current Neuropharmacology An Epigenetic Approach to Pancreatic Cancer Treatment: The Prospective Role of Histone Deacetylase Inhibitors
Current Cancer Drug Targets MET and ALK as Targets for the Treatment of NSCLC
Current Pharmaceutical Design Dry Age-Related Macular Degeneration: Recent Progress of Therapeutic approaches
Current Molecular Pharmacology