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Author: Elliot Goodfellow Publisher: ISBN: Category : Languages : en Pages :
Book Description
"According to the most recent Canadian statistics, the expected likelihood of women developing either breast or ovarian cancer throughout their lifetime is 26.1% and 2.9% respectively. Furthermore, breast cancer in women is the most prominent in the list of expected cancer development and its percentage is approximately twofold that of second place: lung cancer. Common to both men and women, pancreatic cancer has a 2.4% and 2.5% incidence of development respectively. In the previous decade, a commonality in these cancers has been discovered. in that a mutation in DNA repair proteins known as BRCA1 and 2 renders these gene products non-functional. A DNA repair protein, known as poly (ADP-Ribose) polymerase (PARP), then becomes the only means by which mutated cells with defective BRCA gene products can repair DNA. As a result, if PARP is inhibited within mutated cells with defective BRCA gene products, they become incapable of repairing DNA lesions and ultimately undergo cell death. This translated into a novel strategy for the selective therapy of tumours with cancer susceptibility gene termed "synthetic lethality". Despite the successful proof-of-concept for synthetic lethality in the clinic, acquired resistance have been reported. In order to enhance the potency of the approach, we sought to synthesize PARP inhibitors capable of not only blocking PARP function but also alkylating DNA. Thus, we identified EG40, a PARP inhibitor carrying a chloroethyltriazolinium moiety. Using the sulphorhodamine B (SRB) assays, we showed that EG40 is 2.5-fold more potent than its PARP inhibitor counterpart, PARP-4-ANI, and displays 25-fold selectivity for the BRCA2 mutant in an isogenic pair of cell lines. We assessed the binary targeting ability of EG40 using the comet assay to measure the extent of DNA damage, as well as using a PARP assay to measure the extent of PARP inhibition. EG40 inhibits PARP 20-fold more weakly when compared to the naked PARP-4-ANI scaffold and induces significant DNA damage against VC8 mutant cells. In conclusion, we have developed a drug that acts more effectively in terms of potency while maintaining selectivity for its counterpart. Furthermore this drug is effective in inhibiting PARP and causing DNA damage. This gives prima facie evidence that a single molecule termed combi-molecule with dual PARP-DNA targeting function can be highly effective in tumors containing BRCA1 or 2 mutations." --
Author: Elliot Goodfellow Publisher: ISBN: Category : Languages : en Pages :
Book Description
"According to the most recent Canadian statistics, the expected likelihood of women developing either breast or ovarian cancer throughout their lifetime is 26.1% and 2.9% respectively. Furthermore, breast cancer in women is the most prominent in the list of expected cancer development and its percentage is approximately twofold that of second place: lung cancer. Common to both men and women, pancreatic cancer has a 2.4% and 2.5% incidence of development respectively. In the previous decade, a commonality in these cancers has been discovered. in that a mutation in DNA repair proteins known as BRCA1 and 2 renders these gene products non-functional. A DNA repair protein, known as poly (ADP-Ribose) polymerase (PARP), then becomes the only means by which mutated cells with defective BRCA gene products can repair DNA. As a result, if PARP is inhibited within mutated cells with defective BRCA gene products, they become incapable of repairing DNA lesions and ultimately undergo cell death. This translated into a novel strategy for the selective therapy of tumours with cancer susceptibility gene termed "synthetic lethality". Despite the successful proof-of-concept for synthetic lethality in the clinic, acquired resistance have been reported. In order to enhance the potency of the approach, we sought to synthesize PARP inhibitors capable of not only blocking PARP function but also alkylating DNA. Thus, we identified EG40, a PARP inhibitor carrying a chloroethyltriazolinium moiety. Using the sulphorhodamine B (SRB) assays, we showed that EG40 is 2.5-fold more potent than its PARP inhibitor counterpart, PARP-4-ANI, and displays 25-fold selectivity for the BRCA2 mutant in an isogenic pair of cell lines. We assessed the binary targeting ability of EG40 using the comet assay to measure the extent of DNA damage, as well as using a PARP assay to measure the extent of PARP inhibition. EG40 inhibits PARP 20-fold more weakly when compared to the naked PARP-4-ANI scaffold and induces significant DNA damage against VC8 mutant cells. In conclusion, we have developed a drug that acts more effectively in terms of potency while maintaining selectivity for its counterpart. Furthermore this drug is effective in inhibiting PARP and causing DNA damage. This gives prima facie evidence that a single molecule termed combi-molecule with dual PARP-DNA targeting function can be highly effective in tumors containing BRCA1 or 2 mutations." --
Author: Atta ur-Rahman Publisher: Bentham Science Publishers ISBN: 9811487367 Category : Medical Languages : en Pages : 217
Book Description
Frontiers in Anti-Cancer Drug Discovery is a book series devoted to publishing the latest advances in anti-cancer drug design and discovery. In each volume, eminent scientists contribute reviews relevant to all areas of rational drug design and drug discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. The book series should prove to be of interest to all pharmaceutical scientists involved in research in anti-cancer drug design and discovery. The book series is essential reading to all scientists involved in drug design and discovery who wish to keep abreast of rapid and important developments in the field. This volume of the series focuses on reviews of treatments derived from natural sources (cannabinoid-based medicines and turmeric), immunotherapy, biomarkers for glioblastoma and some new drug targets for anti-cancer treatment. The reviews included in this volume are: - Cannabinoid-Based Anticancer Strategies: - The Beneficial Effects of Turmeric and Its Active Constituent in Cancer Treatment - Immunotherapy Approaches Focusing on Cancer Stem Cells - Immunotherapy for the Treatment of Hepatocellular Carcinoma - Role of Biomarkers in Developing Therapies for Glioblastoma Multiforme - Poly (ADP-ribose) Polymerases as New Drug Targets in Cancer Treatment
Author: Nandini Dey Publisher: Humana Press ISBN: 3319342118 Category : Medical Languages : en Pages : 307
Book Description
In the post human-genome project era, cancer specific genomic maps are redesigning tumor taxonomy by evolving from histopathology to molecular pathology. The success of a cancer drug today is fundamentally based on the success in identifying target genes that control beneficial pathways. The overwhelming power of genomics and proteomics has enlightened researchers about the fact that the PI3K-mTOR pathway is the most commonly up-regulated signal transduction pathway in various cancers, either by virtue of its activation downstream of many cell surface growth factor receptors or by virtue of its collateral and compensatory circuitry with RAS-MAPK pathway. Oncogenic signaling in the majority of solid tumors is sustained via the PI3K-AKT-mTOR pathway. Because of its prominent role in many cancer types, the PI3K-mTOR pathway has become a major therapeutic target. The volume includes two complementary parts which address the problem of etiology and disease progression and is intended to portray the very basic mechanisms of the PI3K-AKT-mTOR signaling pathway’s involvement in various facets of the cancer, including stem cell renewal, cell metabolism, angiogenesis, genetic instability, and drug resistance. Significant progress has been made in recent years elucidating the molecular mechanism of cancer cell proliferation, angiogenesis, and drug-resistance in relation to the PI3K-mTOR pathway and this volume provides an in-depth overview of recent developments made in this area.
Author: Alexander Bürkle Publisher: Springer Science & Business Media ISBN: 0387360050 Category : Medical Languages : en Pages : 260
Book Description
This is the most comprehensive, up-to-date reference on this post-translational modification of proteins, which is intimately linked with DNA repair, maintenance of genomic stability, transcriptional regulation, cell death and a variety of other cellular phenomena as well as with a variety of pathophysiological conditions, including ischemia-reperfusion damage, Parkinson’s disease, Type I diabetes mellitus, hemorrhagic and septic shock and other inflammatory conditions. Richly illustrated, it offers 19 chapters written by international experts.
Author: Seigo Nakamura Publisher: Springer Nature ISBN: 9811645213 Category : Medical Languages : en Pages : 324
Book Description
This highly informative and clearly written book presents the basic science and the latest data on hereditary breast and ovarian cancer (HBOC) to provide an up-to-date and holistic overview of the disease. It starts off by presenting the molecular mechanisms, genetic testing and counseling, and variants of unknown significance (VUS) to help readers understand the contemporary interpretation of the disease. Further chapters focus on the surveillance, diagnosis and treatment, including chemoprevention, risk reduction and drug development based on molecular mechanisms. It also includes a chapter on the latest findings from the HBOC database, ethical issues and the parp inhibitors, and discusses innovative thinking to manage and understand the disease. Hereditary Breast and Ovarian Cancer - Molecular Mechanism and Clinical Practice offers breast surgeons, medical oncologists, gynecological oncologists and genetic counselors a comprehensive overview of the disease. Providing insights into recent scientific findings and further avenues for investigation, it is also a thought-provoking and informative read for researchers and scholars.
Author: Keshav Lalit Ameta Publisher: Springer Nature ISBN: 981190832X Category : Science Languages : en Pages : 465
Book Description
This book presents an overview of the recent advancements for the synthesis of small- and medium-sized azaheterocycles, including pyrroles, indoles, pyrimidines, pyridines, pyrrolidines, imidazoles, pyrazoles, pyrazolines, lactams, and 1,2,3-triazoles, which are significant scaffolds for compounds with pharmaceutical uses. The book also discusses various properties and performance attributes of azaheterocycles including their bioactivity and synthetic strategies. Given the contents, the book will be a valuable reference for students, researchers, and professionals interested in organic synthesis and medicinal chemistry.
Author: J¿nos Fischer Publisher: John Wiley & Sons ISBN: 3527344683 Category : Medical Languages : en Pages : 270
Book Description
Provides unique insider insight into the current drug development process, and what it takes to achieve success In this fourth volume in the series, inventors and primary developers of drugs that made it to the market continue telling the story of the drugs? discovery and development, and discuss the sometimes twisted route from the first drug candidate molecule to the final marketed one. Beginning with a general section addressing overarching topics for drug discovery, the book offers seven chapters that feature selected case studies describing recently introduced drugs or drug classes. These include small molecule drugs as well as biopharmaceuticals and range across different therapeutic fields. Together, they provide a representative cross-section of the present-day drug development effort. Successful Drug Discovery: Volume 4 covers trends in peptide-based drug discovery and the physicochemical properties of recently approved oral drugs. The section on drug class studies looks at antibody-drug conjugates and the discovery, evolution, and therapeutic potential of dopamine partial agonists. Featured case studies examine the discovery of Etelcalcetide for the treatment of secondary hyper-parathyroidism in patients with chronic kidney disease; the development of Lenvatinib Mesylate; the discovery and development of Venetoclax; and more. -Focuses on recently introduced drugs that have not been featured in any textbooks or general references, including Ocrelizumab, a new generation of anti-CD-20 mAb for the treatment of multiple sclerosis, and Venetoclax, a selective antagonist of BCL-2 -Features personal experiences of successful drug developers from industry and academia -Endorsed and supported by the International Union of Pure and Applied Chemistry (IUPAC) Successful Drug Discovery: Volume 4 provides a fascinating and informative look into the process of drug discovery and would be a great reference for those in the pharmaceutical industry, organic and pharmaceutical chemists, and lecturers in pharmacy.
Author: Steven Howard Publisher: Royal Society of Chemistry ISBN: 1782625658 Category : Medical Languages : en Pages : 314
Book Description
Fragment-based drug discovery is a rapidly evolving area of research, which has recently seen new applications in areas such as epigenetics, GPCRs and the identification of novel allosteric binding pockets. The first fragment-derived drug was recently approved for the treatment of melanoma. It is hoped that this approval is just the beginning of the many drugs yet to be discovered using this fascinating technique. This book is written from a Chemist's perspective and comprehensively assesses the impact of fragment-based drug discovery on a wide variety of areas of medicinal chemistry. It will prove to be an invaluable resource for medicinal chemists working in academia and industry, as well as anyone interested in novel drug discovery techniques.
Author: Beverley Isherwood Publisher: Royal Society of Chemistry ISBN: 1839160799 Category : Medical Languages : en Pages : 273
Book Description
Phenotypic drug discovery has been highlighted in the past decade as an important strategy in the discovery of new medical entities. How many marketed drugs are derived from phenotypic screens? From the most recent examples, what were the factors enabling target identification and validation? This book answers these questions by elaborating on fundamental capabilities required for phenotypic drug discovery and using case studies to illustrate approaches and key success factors. Written and edited by experienced practitioners from both industry and academia, this publication will equip researchers with a thought-provoking guide to the application and future development of contemporary phenotypic drug discovery for clinical success.
Author: United States. Public Health Service. Office of the Surgeon General Publisher: ISBN: Category : Government publications Languages : en Pages : 728
Book Description
This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.
Author: Elliot Goodfellow
Author: Elliot Goodfellow
Author: Atta ur-Rahman
Author: Nandini Dey
Author: Alexander Bürkle
Author: Seigo Nakamura
Author: Keshav Lalit Ameta
Author: J¿nos Fischer
Author: Steven Howard
Author: Beverley Isherwood
Author: United States. Public Health Service. Office of the Surgeon General