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 |
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
-
Identification of AHSA1 as a Potential Therapeutic Target for Breast
Cancer: Bioinformatics Analysis and <i>in vitro</i> Studies
Current Cancer Drug Targets In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System
Current Pharmaceutical Biotechnology Approaches to Improve Efficiency of Dendritic Cell-based Therapy of High Grade Gliomas
Current Pharmaceutical Design siRNA-Mediated Knock-Down of P-Glycoprotein Expression Reveals Distinct Cellular Disposition of Anticancer Tyrosine Kinases Inhibitors
Drug Metabolism Letters Pancreatic Cancer and Personalized Medicine: Can Genomics Facilitate Early Diagnosis or Improve Therapeutic Outcomes?
Current Pharmacogenomics and Personalized Medicine ABC Transporters and Drug Resistance in Patients with Epilepsy
Current Pharmaceutical Design Cellular FLICE-Like Inhibitory Protein (C-FLIP): A Novel Target for Cancer Therapy
Current Cancer Drug Targets Emerging Role of ImmunoPET in Receptor Targeted Cancer Therapy
Current Drug Delivery ALK-Positive Non-Small Cell Lung Cancer; Potential Combination Drug Treatments
Current Cancer Drug Targets The Use of SIFT-MS in Profiling the Faecal Volatile Metabolome in Horses with Colic: A Pilot Study
Current Analytical Chemistry The Effect of ACT on Self-Esteem and Self-efficacy of Women with Breast Cancer in Iran
Current Women`s Health Reviews Current Management of Neonatal Neuroblastoma
Current Pediatric Reviews Novel Classes of Dimer Antitumour Drug Candidates
Current Pharmaceutical Design Novel Histone Deacetylase Inhibitors for the Treatment of Pediatric Brain Tumors
Central Nervous System Agents in Medicinal Chemistry Serum miR-372 is a Diagnostic and Prognostic Biomarker in Patients with Early Colorectal Cancer
Anti-Cancer Agents in Medicinal Chemistry Suppression of Glial HO-1 Activitiy as a Potential Neurotherapeutic Intervention in AD
Current Alzheimer Research Sulfotransferase 1A1 as a Biomarker for Susceptibility to Carcinogenesis: From Molecular Genetics to the Role of Dietary Flavonoids
Current Drug Metabolism Micro/Nanoparticle Design and Fabrication for Pharmaceutical Drug Preparation and Delivery Applications
Current Drug Therapy MYC-Mediated Synthetic Lethality for Treating Tumors
Current Cancer Drug Targets Modulation of ABC Transporters by Nuclear Receptors: Physiological, Pathological and Pharmacological Aspects
Current Medicinal Chemistry