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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.
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
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.
Enables drug developers in academia and industry to expand the range of accessible drug targets through induced protein degradation Since the introduction of the PROTAC technology in 2015, targeted protein degradation has greatly increased the range of druggable protein targets, 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 range of druggable targets. In Inducing Targeted Protein Degradation, readers will find the most recent information on: Cellular mechanisms of targeted protein degradation and current approaches to retarget these mechanisms for therapeutic use A comparison of different induced degradation approaches, including PROTAC, light-activated degradation, and CHAMPS Drug development aspects such as DMPK optimization and selection of clinical candidates A discussion of the potential of targeted degradation for expanding the range of druggable protein targets 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.
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.
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.
A Top 25 CHOICE 2016 Title, and recipient of the CHOICE Outstanding Academic Title (OAT) Award. How much energy is released in ATP hydrolysis? How many mRNAs are in a cell? How genetically similar are two random people? What is faster, transcription or translation?Cell Biology by the Numbers explores these questions and dozens of others provid
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.
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.
Platform Technologies in Drug Discovery and Validation, Volume 50, the latest release in the Annual Reports in Medicinal Chemistry series, provides timely and critical reviews of important topics in medicinal chemistry, with an emphasis on emerging topics in the biological sciences. Topics covered in this new volume include DELT, Oligos: ASO, siRNA, CRISPR, Micro-fluidic chemistry, High throughput screening, Kinase-centric computational drug development, Virtual Screening, Phenotypic screening, PROTACS, Chemical Biology, Fragment-based lead generation, Antibody-Drug Conjugates, Antibody-recruiting small molecules, Deuteration, and Peptides. Unique for its treatment of platform technologies for medicinal chemistry and target validation Provides a single, rich volume that summaries a broad spectrum of expertise relevant to the field Presents state-of-the-art summaries of platform technologies