Abstract
Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy. Since the early benzamide inhibitors of the 1980s PARP inhibitors, developed through structure-activity relationships and crystal structure-based drug design, that are 1,000x more potent have been identified. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies and are now under clinical evaluation. PARP inhibitors can also selectively kill cells and tumours with homozygous defects in the hereditary breast cancer genes, BRCA1 and BRCA2.
Keywords: Base excision repair/single strand break repair, Poly(ADP-ribose) polymerase-1 (PARP-1), PARP inhibitors
Anti-Cancer Agents in Medicinal Chemistry
Title: PARP Inhibitor Development for Systemic Cancer Targeting
Volume: 7 Issue: 5
Author(s): Tomasz Zaremba and Nicola Jane Curtin
Affiliation:
Keywords: Base excision repair/single strand break repair, Poly(ADP-ribose) polymerase-1 (PARP-1), PARP inhibitors
Abstract: Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy. Since the early benzamide inhibitors of the 1980s PARP inhibitors, developed through structure-activity relationships and crystal structure-based drug design, that are 1,000x more potent have been identified. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies and are now under clinical evaluation. PARP inhibitors can also selectively kill cells and tumours with homozygous defects in the hereditary breast cancer genes, BRCA1 and BRCA2.
Export Options
About this article
Cite this article as:
Zaremba Tomasz and Curtin Jane Nicola, PARP Inhibitor Development for Systemic Cancer Targeting, Anti-Cancer Agents in Medicinal Chemistry 2007; 7 (5) . https://dx.doi.org/10.2174/187152007781668715
DOI https://dx.doi.org/10.2174/187152007781668715 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
- 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
-
Lanthionine Synthetase Component C-Like Protein 2: A New Drug Target for Inflammatory Diseases and Diabetes
Current Drug Targets Natural Products as Anti-Cancerous Therapeutic Molecules Targeted towards Topoisomerases
Current Protein & Peptide Science The Potential Anti-Tumorigenic and Anti-Metastatic Side of the Proprotein Convertases Inhibitors
Recent Patents on Anti-Cancer Drug Discovery Radionuclides Used in Nuclear Medicine Therapy – From Production to Dosimetry
Current Medical Imaging Design, Synthesis and Biological Evaluation of 3-(3,4,5-Trimethoxyphenyl)- 5-(2-(5-arylbenzo[b]thiophen-3-yl)oxazol-5-yl)isoxazole Derivatives as Anticancer Agents
Letters in Organic Chemistry Azathioprine, Mucosal Healing in Ulcerative Colitis, and the Chemoprevention of Colitic Cancer: A Clinical-Practice-Based Forecast
Inflammation & Allergy - Drug Targets (Discontinued) Targeting the SUMO E2 Conjugating Enzyme Ubc9 Interaction for Anti-Cancer Drug Design
Anti-Cancer Agents in Medicinal Chemistry Co-Delivery of Epirubicin and siRNA Using Functionalized Mesoporous Silica Nanoparticles Enhances In vitro and In vivo Drug Efficacy
Current Drug Delivery Alternative Splice Variants of Survivin as Potential Targets in Cancer
Current Drug Discovery Technologies Small Molecule Inhibitors of NF-κB and JAK/STAT Signal Transduction Pathways as Promising Anti-Inflammatory Therapeutics
Mini-Reviews in Medicinal Chemistry PDZ Domain Protein-Protein Interactions: A Case Study with PICK1
Current Topics in Medicinal Chemistry Chronic Migraineurs Form Carboxyhemefibrinogen and Iron-Bound Fibrinogen
CNS & Neurological Disorders - Drug Targets Stem Cell-Derived Microvesicles: A Cell Free Therapy Approach to the Regenerative Medicine
Current Biotechnology Dendrimer-Curcumin Conjugate: A Water Soluble and Effective Cytotoxic Agent Against Breast Cancer Cell Lines
Anti-Cancer Agents in Medicinal Chemistry Impact of Drug Metabolism/Pharmacokinetics and their Relevance Upon Traditional Medicine-based Cardiovascular Drug Research
Current Drug Metabolism Rab GTPases, Membrane Trafficking and Diseases
Current Drug Targets Psoriasis in Children: A Review
Current Pediatric Reviews Smad7 and its Potential as Therapeutic Target in Inflammatory Bowel Diseases
Current Drug Metabolism Perspectives on Sesquiterpene Lactones in Inflammation and Cancer
Current Drug Targets A Hybrid Binary Cuckoo Search and Genetic Algorithm for Feature Selection in Type-2 Diabetes
Current Bioinformatics