Download or read book Inducing Targeted Protein Degradation written by Philipp Cromm and published by John Wiley & Sons. This book was released on 2022-11-15 with total page 389 pages. Available in PDF, EPUB and Kindle. Book excerpt: Inducing Targeted Protein Degradation Enables drug developers in academia and industry to expand the range of accessible drug targets through induced protein degradation Since the breakthrough of the PROTAC technology in 2015, targeted protein degradation has revolutionized drug discovery, enabling pharma companies to develop completely novel therapeutics. Inducing Targeted Protein Degradation is a timely guide to navigating the complexities of the subject and understanding its practical application, with an eye on expanding the druggable space. In Inducing Targeted Protein Degradation, readers will find the most recent information on: Cellular mechanisms of targeted protein degradation and current approaches to utilize these mechanisms for drug discovery A comparison of different induced degradation approaches, including PROTAC, molecular glues, LYTACs and ATTECs as well as additional post translational modifications Drug development aspects such as DMPK optimization and criteria for the selection of clinical candidates A discussion of the potential of targeted degradation for expanding the druggable space Inducing Targeted Protein Degradation will serve as a practice-oriented reference on induced protein degradation for drug discovery professionals and for researchers employing chemical biology approaches.
Download or read book Targeted Protein Degradation written by Angela M. Cacace and published by Humana. This book was released on 2021-08-26 with total page 351 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume contains a collection of innovative techniques for studying targeted protein degradation. Chapters guide readers through heterobifunctional proteolysis-targeting chimeras (PROTACs) approaches, E3 ligase, E3 ligase-induced ubiquitylation, proteomic approaches, novel degrader molecules, molecular glue, and stabilize binding interaction between a target and E3 ubiquitin ligase. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and reagents, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Targeted Protein Degradation: Methods and Protocols aims to ensure successful results in this emerging field of drug discovery.
Download or read book Protein Degradation with New Chemical Modalities written by Craig Crews and published by Royal Society of Chemistry. This book was released on 2020-10-08 with total page 382 pages. Available in PDF, EPUB and Kindle. Book excerpt: Targeting protein degradation using small molecules is one of the most exciting small-molecule therapeutic strategies in decades and a rapidly growing area of research. In particular, the development of proteolysis targeting chimera (PROTACs) as potential drugs capable of recruiting target proteins to the cellular quality control machinery for elimination has opened new avenues to address traditionally 'difficult to target' proteins. This book provides a comprehensive overview from the leading academic and industrial experts on recent developments, scope and limitations in this dynamically growing research area; an ideal reference work for researchers in drug discovery and chemical biology as well as advanced students.
Download or read book New Chemical Approaches for the Development of Targeted Protein Degradation written by Hannah Lithgow and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules which induce targeted protein degradation by redirecting the ubiquitin-proteasome system. PROTACs simultaneously bind to both a protein of interest and an E3 ubiquitin ligase. The proximity of the target protein and the E3 ligase complex allows transfer of ubiquitin onto the target protein, after which the protein can be recognised and then degraded by the proteasome. The PROTAC mechanism-of-action offers a number of potential advantages over small molecule inhibition for the development of new medicines. Efficacy maybe achieved from low doses, extended duration of action is possible, arising from pharmacokinetic pharmacodynamic disconnects, and challenging targets may become tractable through the identification of suitable affinity binders. In this research, the development of PROTAC technology is explored. In order to expand the breadth of E3 ligases that are currently recruited using this approach, a promiscuous toolbox was established to prosecute new chemical matter for E3 ligases. In order to further elaborate the promiscuous toolbox already known for the degradation of kinases, investigation of a promiscuous bromodomain PROTAC was explored. After assessment of bromosporine derived PROTACs in multiple cell lines with two validated E3 ligases, it was deemed an unsuitable binder for the toolbox. The PROTACs were unable to induce potent nor promiscuous bromodomain degradation. As a result, a known BET bromodomain binder was selected for the promiscuous toolbox in addition to the known promiscuous kinase binder and a RIPK2 binder for new E3 ligase validation. With a promiscuous toolbox in hand, a new E3 ligase was evaluated. Indisulam, a small molecule "molecular glue", was found to bind to the E3 ligase DCAF15. Indisulam derived PROTACs were synthesised and evaluated with a range of linker lengths and multiple protein binders. These studies conclusively demonstrated that protein degradation was not achieved using these PROTACs. The indisulam derived binder was subsequently found not to be suitable for the PROTAC approach without further investigation to determine DCAF15 recruitment. Given the lack of degradation with the initial, empirically selected E3 ligases from the literature, a distinct E3 ligase agnostic approach to protein degradation was developed. A high throughput phenotypic screen was established using green fluorescent protein (GFP) as the protein of interest, where cellular fluorescence levels correlate with protein degradation. High throughput chemistry techniques were implemented and optimised to synthesise thousands of HaloCompounds in-situ by amide coupling. The compounds were tested directly in cells to find new chemical matter for the induction of protein degradation. This strategy allowed identification of several potential hits from a 3000-amine screen, with one high-confidence hit currently being further evaluated. For this effort the screen was optimised successfully and can potentially be employed for a target-agnostic high-throughput screening campaign of hundreds of thousands of compounds for new E3 ligases to employ in future protein degradation strategies.
Download or read book Targeted Protein Degradation written by and published by Elsevier. This book was released on 2023-02-08 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: Targeted Protein Degradation, Volume 680 in the Methods in Enzymology series, highlights new advances in the field with this new volume presenting interesting chapters on a variety of timely topics, with each. Each written by an international board of authors. - Provides the authority and expertise of leading contributors from an international board of authors - Presents the latest release in Methods in Enzymology serials - Updated release includes the latest information on Targeted Protein Degradation
Download or read book Adverse Effects of Cancer Chemotherapy Anything New to Improve Tolerance and Reduce Sequelae written by Kulmira Nurgali and published by Frontiers Media SA. This book was released on 2018-06-12 with total page 245 pages. Available in PDF, EPUB and Kindle. Book excerpt: Advances in anti-cancer chemotherapy over recent years have led to improved efficacy in curing or controlling many cancers. Some chemotherapy-related side-effects are well recognized and include: nausea, vomiting, bone marrow suppression, peripheral neuropathy, cardiac and skeletal muscle dysfunction and renal impairment. However, it is becoming clearer that some chemotherapy-related adverse effects may persist even in long term cancer survivors. Problems such as cognitive, cardiovascular and gastrointestinal dysfunction, and neuropathy may lead to substantial long term morbidity. Despite improvements in treatments to counteract acute chemotherapy-induced adverse effects, they are often incompletely effective. Furthermore, counter-measures for some acute side-effects and many potential longer term sequelae of anti-cancer chemotherapy have not been developed. Thus, new insights into prevalence and mechanisms of cancer chemotherapy-related side effects are needed and new approaches to improving tolerance and reduce sequelae of cancer chemotherapy are urgently needed. The present Research Topic focuses on adverse effects and sequelae of chemotherapy and strategies to counteract them.
Download or read book Successful Drug Discovery Volume 5 written by Janos Fischer and published by John Wiley & Sons. This book was released on 2021-02-12 with total page 340 pages. Available in PDF, EPUB and Kindle. Book excerpt: Filled with unique insights into current drugs that have made it to the marketplace In the fifth volume of Successful Drug Discovery, the inventors and primary developers of drugs that made it to the market tell the story of the drugs discovery and development. Case studies of drugs from different therapeutic fields reveal the all-too-often unpredictable path from the first drug candidate molecule to the successfully marketed drug. In addition, this new volume addresses overarching topics for drug discovery, such as drug discovery in academia, and discusses currently important classes of small molecule as well as biological drugs. Comprehensive in scope, the books nine chapters provide a representative cross-section of the present-day drug development effort. The authoritative fifth volume is filled with relevant data and chemical information, as well as the insight and experience of the best contemporary drug creators. This important volume: - Puts the focus on recently introduced drugs that have not yet made it into standard textbooks or general references - Contains information and insight that is new and often not even available from the primary literature - Reveals what it takes to successfully develop a drug molecule that has made it all the way to the market - Is endorsed and supported by the International Union of Pure and Applied Chemistry (IUPAC) Written for medicinal chemists, pharmaceutical chemists, organic chemists, Successful Drug Discovery, Volume Five reveals the most recent techniques used by drug innovators in the drug development process.
Download or read book Dark Remedy written by Trent Stephens and published by Basic Books. This book was released on 2009-04-27 with total page 244 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this riveting medical detective story, Trent Stephens and Rock Brynner recount the history of thalidomide, from the epidemic of birth defects in the 1960's to the present day, as scientists work to create and test an alternative drug that captures thalidomide's curative properties without its cruel side effects. A parable about compassion-and the absence of it-Dark Remedy is a gripping account of thalidomide's extraordinary impact on the lives of individuals and nations over half a century.
Download or read book Targeted Protein Degradation as a New Approach to Drug Discovery written by Christopher Patrick Tinworth and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proteolysis targeting chimeras (Protacs) are heterobifunctional small molecules which induce targeted protein degradation by hijacking the natural intracellular quality control mechanism, the ubiquitin-proteasome system. Protacs simultaneously bind both a target protein and an E3 ubiquitin ligase, forming a ternary complex. The close proximity of the target protein and the E3 ligase allows transfer of the post-translational modifier ubiquitin onto the target protein, which allows the protein to be recognised and degraded into small peptidic fragments by the proteasome. The Protac approach offers several advantages over small-molecule inhibition alone as efficacy can be driven from low drug concentrations, extended duration of action can be achieved, and scaffolding functions of the target protein can be removed. In this thesis, the application of Protac technology towards a series of disease-relevant proteins is explored. In Chapters 2 and 3, Protacs targeting the kinase ActR2B and the thyroid hormone receptor were developed as potential treatments for sarcopenia and hyperthyroidism, respectively. However, in both cases, no target degradation was observed. Given the lack of degradation with the initial empirically selected targets, a distinct, non-selective approach to protein degradation was considered in Chapter 4. Protacs based on a highly promiscuous kinase inhibitor were designed and synthesised, then profiled using proteome-wide expression proteomics. This strategy allowed identification of several novel degradable targets, and also indicated proteins that may be more challenging to degrade. The opportunity for degradation selectivity in the absence of binding selectivity was also highlighted. Having identified Bruton's tyrosine kinase (BTK) as one of these degradable targets, selective BTK Protacs were then studied in Chapter 5. Protacs based on the covalent inhibitor Ibrutinib led to the surprising discovery that covalent inhibition prevents Protac-mediated degradation of BTK. Protacs developed from a selective, reversible BTK inhibitor allowed rapid interrogation of the kinase as a prototypical Protac target.
Download or read book Activity Based Protein Profiling written by Benjamin F. Cravatt and published by Springer. This book was released on 2019-01-25 with total page 420 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume provides a collection of contemporary perspectives on using activity-based protein profiling (ABPP) for biological discoveries in protein science, microbiology, and immunology. A common theme throughout is the special utility of ABPP to interrogate protein function and small-molecule interactions on a global scale in native biological systems. Each chapter showcases distinct advantages of ABPP applied to diverse protein classes and biological systems. As such, the book offers readers valuable insights into the basic principles of ABPP technology and how to apply this approach to biological questions ranging from the study of post-translational modifications to targeting bacterial effectors in host-pathogen interactions.
Download or read book Molecular Biology of the Cell written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Antiviral Drug Discovery and Development written by Xinyong Liu and published by Springer Nature. This book was released on 2021-07-13 with total page 357 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book summarizes state-of-the-art antiviral drug design and discovery approaches starting from natural products to de novo design, and provides a timely update on recently approved antiviral drugs and compounds in advanced clinical development. Special attention is paid to viral infections with a high impact on the world population or highly relevant from the public health perspective (HIV, hepatitis C, influenza virus, etc.). In these chapters, limitations associated with adverse effects and emergence of drug resistance are discussed in detail. In addition to classical antiviral strategies, chapters will be dedicated to discuss the non-classical drug development strategies to block viral infection, for instance, allosteric inhibitors, covalent antiviral agents, or antiviral compounds targeting protein–protein interactions. Finally, current prospects for producing broad-spectrum antiviral inhibitors will be also addressed. The book is distinctive in providing the most recent update in the rapidly evolving field of antiviral therapeutics. Authoritative reviews are written by international scientists well known for their contributions in their topics of research, which makes this book suitable for researchers not only within the antiviral research community but also attractive to a broad audience in the drug discovery field. This book covers molecular structures and biochemical mechanisms mediating the antiviral effects, while discussing various ligand design strategies, which include traditional medicinal chemistry, computational chemistry, and chemical biology approaches. The book provides a comprehensive review of antiviral drug discovery and development approaches, particularly focusing on current innovations and future trends.
Download or read book Autophagy Biology and Diseases written by Zheng-Hong Qin and published by Springer Nature. This book was released on 2019-11-27 with total page 727 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book series consists of 3 volumes covering the basic science (Volume 1), clinical science (Volume 2) and the technology and methodology (Volume 3) of autophagy. Volume 1 focuses on the biology of autophagy, including the signaling pathways, regulating processes and biological functions. Autophagy is a fundamental physiological process in eukaryotic cells. It not only regulates normal cellular homeostasis, and organ development and function, but also plays an important role in the pathogenesis of a wide range of human diseases. Thanks to the rapid development of molecular biology and omic technologies, research on autophagy has boomed in recent decades, and more and more cellular and animal models and state-of the-art technologies are being used to shed light on the complexity of signaling networks involved in the autophagic process. Further, its involvement in biological functions and the pathogenesis of various diseases has attracted increased attention around the globe. Presenting cutting-edge knowledge, this book series is a useful reference resource for researchers and clinicians who are working on or interested in autophagy.
Download or read book Inhibitors of Protein Protein Interactions written by Ali Tavassoli and published by Royal Society of Chemistry. This book was released on 2020-12-07 with total page 357 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein-protein interactions (PPI) are at the heart of the majority of cellular processes, and are frequently dysregulated or usurped in disease. Given this central role, the inhibition of PPIs has been of significant interest as a means of treating a wide variety of diseases. However, there are inherent challenges in developing molecules capable of disrupting the relatively featureless and large interfacial areas involved. Despite this, there have been a number of successes in this field in recent years using both traditional drug discovery approaches and innovative, interdisciplinary strategies using novel chemical scaffolds. This book comprehensively covers the various aspects of PPI inhibition, encompassing small molecules, peptidomimetics, cyclic peptides, stapled peptides and macrocycles. Illustrated throughout with successful case studies, this book provides a holistic, cutting-edge view of the subject area and is ideal for chemical biologists and medicinal chemists interested in developing PPI inhibitors.
Download or read book CRC Handbook of Organic Photochemistry and Photobiology written by Axel G. Griesbeck and published by CRC Press. This book was released on 2012 with total page 943 pages. Available in PDF, EPUB and Kindle. Book excerpt: This title includes research from experts in organic chemistry & many other disciplines. There are sections on new terminology, the usefulness of particular reactions & experimental details.
Download or read book Intracellular Protein Degradation written by A.J. Rivett and published by Elsevier Science. This book was released on 1998-08-07 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume brings together a set of reviews that provide a summary of our current knowledge of the proteolytic machinery and of the pathways of protein breakdown of prokaryotic and eukaryotic cells. Intracellular protein degradation is much more than just a mechanism for the removal of incorrectly folded or damaged proteins. Since many short-lived proteins have important regulatory functions, proteolysis makes a significant contribution to many cellular processes including cell cycle regulation and transciptional control. In addition, limited proteolytic cleavage can provide a rapid and efficient mechanism of enzyme activation or inactivation in eukaryotic cells. In the first chapter, Maurizi provides an introduction to intracellular protein degradation, describes the structure and functions of bacterial ATP-dependent proteases, and explores the relationship between chaperone functions and protein degradation. Many of the principles also apply to eukaryotic cells, although the proteases involved are often not the same. Interestingly, homologues of one of the bacterial proteases, Ion protease, have been found in mitochondria in yeast and mammals, and homologues of proteasomes, which are found in all eukaryotic cells (see below), have been discovered in some eubacteria. Studies of proteolysis in yeast have contributed greatly to the elucidation of both lysosomal (vacuolar) and nonlysosomal proteolytic pathways in eukaryotic cells. Thumm and Wolf (chapter 2) describe studies that have elucidated the functions of proteasomes in nonlysosomal proteolysis and the contributions of lysosomal proteases to intracellular protein breakdown. Proteins can be selected for degradation by a variety of differen mechanisms. The ubiquitin system is one complex and highly regulated mechanism by which eukaryotic proteins are targetted for degradation by proteosomes. In chapter 3, Wilkinson reviews the components and functions of the ubiquitin system and considers some of the known substrates for this pathway which include cell cycle and transcriptional regulators. The structure and functions of proteosomes and their regulatory components are described in the two subsequent chapters by Tanaka and Tanahashi and by Dubiel and Rechsteiner. Proteasomes were the first known example of threonine proteases. They are multisubunit complexes that, in addition to being responsible for the turnover of most short-lived nuclear and cytoplasmic protein, are also involved in antigen processing for presentation by the MHC class I pathway. Recent studies reviewed by McCracken and colleagues (chapter 6) lead to the exciting conclusion that some ER-associated proteins are degraded by cytosolic proteasomes. Lysosomes are responsible for the degradation of long-lived proteins and for the enhanced protein degradation observed under starvation conditions. In chapter 7 Knecht and colleagues review the lysosomal proteases and describe studies of the roles of lysosomes and the mechanisms for protein uptake into lysosomes. Methods of measuring the relative contribution of different proteolytic systems (e.g., ubiquitin-proteasome pathway, calcium-dependent proteases, lysosomes) to muscle protein degradation, and the conclusions from such studies, are reviewed by Attai and Taillinder in the following chapter. Finally, proteases play an important role in signaling apoptosis by catalyzing the limited cleavage of enzymes. Mason and Beyette review the role of the major players, caspases, which are both activated by and catalyze limite proteolysis, and also consider the involvement of other protoelytic enzymes in this pathway leading cell death.
Download or read book HSF1 and Molecular Chaperones in Biology and Cancer written by Marc Laurence Mendillo and published by Springer Nature. This book was released on 2020-04-15 with total page 185 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein homeostasis, or “Proteostasis”, lies at the heart of human health and disease. From the folding of single polypeptide chains into functional proteins, to the regulation of intracellular signaling pathways, to the secreted signals that coordinate cells in tissues and throughout the body, the proteostasis network operates to support cell health and physiological fitness. However, cancer cells also hijack the proteostasis network and many of these same processes to sustain the growth and spread of tumors. The chapters in this book are written by world experts in the many facets of the proteostasis network. They describe cutting-edge insights into the structure and function of the major chaperone and degradation systems in healthy cells and how these systems are co-opted in cancer cells and the cells of the tumor microenvironment. The chapters also cover therapeutic interventions such as the FDA-approved proteasome inhibitors Velcade and Krypolis as well as other therapies currently under clinical investigation to disarm the ability of the proteostasis network to support malignancy. This compendium is the first of its kind and aims to serve as a reference manual for active investigators and a primer for newcomers to the field. This book is dedicated to the memory of Susan Lindquist, a pioneer of the proteostasis field and a champion of the power of basic scientific inquiry to unlock the mechanisms of human disease. The chapter “Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective” is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.
