Overview

This book aims to provide a comprehensive examination of the field of molecular chaperone inhibition and its application to pharmaceutical research. With several small molecule inhibitors in oncology clinical development, there is clearly intense interest in the chaperones as a molecular target. Filling a significant gap in the market by providing a detailed comparison of discovery programs across the industry, this text will find broad interest among researchers in the field of molecular chaperone pharmaceutical research, oncology research, and medicinal chemistry. Arranged into three main sections the book covers structure and function, small molecule inhibitors and concludes with a section discussing clinical perspectives. With specific chapters covering the discovery of key molecules such as, BIIB028, STA-9090, Serenex Hsp90 inhibitor, NVP-AUY922 and NVP-HSP990, this comprehensive text is an essential treatise for researchers working in academia and industry.

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9781849736664

Table of Contents

Reviews

...this 422- page volume adds greatly to the discussion by reporting many of the more recent advances in targeting Hsp90, whilst including an elegant overview of the advances in Hsp70 research, an area that has received considerably less re- search attention until more recently. The editors have assembled work from a variety of leading experts in the molecular chaperone field... ...the authors have produced an outstanding overview of the subject that will be an extremely useful account for a wide variety of scientists... ...the authors present an excellent and thought-provoking outlook on the future of the subject Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham * Chemmedchem review in March 2015 issue * The final two chapters discuss the targeting of molecular chaperones as therapeutics for important diseases such as malaria and neurological conditions. This is an invaluable addition to the book and, in addition to the Hsp70 discussion, really sets this text apart from the numerous previous review articles and books in the area. On a more critical note, the book be- comes somewhat repetitive in several places and so perhaps more distinction between the chapters could have been achieved. Another slight criticism of the book would be that whilst the majority of chapters have useful, informative figures, a small number of chapters are somewhat lacking in suitable diagrams, particularly chemical structures that would aid the discussion and increase the appeal to chemists. Additionally, in a few chapters the diagrams and structures are rather poor quality (e.g., grainy or squashed), and the chemical structures are formatted inconsistently throughout the book, with some bond angles appearing to have been drawn somewhat haphazardly. Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham * Chemmedchem review in March 2015 issue PART 2 * Since the discovery in the mid-1990s that geldanamycin, a benzo- quinone ansamcin, acts as an inhibitor of heat shock protein 90 (Hsp90), research in this area has boomed. Whilst several topics touched upon in this book have been extensively reviewed to date, this 422- page volume adds greatly to the discussion by reporting many of the more recent advances in targeting Hsp90, whilst including an elegant overview of the advances in Hsp70 research, an area that has received considerably less re- search attention until more recently. The editors have assembled work from a variety of leading experts in the molecular chaperone field to outline the strategies and therapeutic advances in targeting chaperone proteins to combat high-pro- file diseases, predominantly within oncology but also the less researched ap- plication to the treatment of malaria and neurodegenerative diseases. Whilst the book includes details that will provoke interest for those new to the molecular chaperone arena, the majority of the chapters involve in-depth discussion and analysis more suited to experts in the subject. Chapter 1 presents a well-written over- view of molecular chaperones, although it would benefit from some molecular structures to illustrate what is otherwise a very nice analysis of various small-molecule chaperone inhibitors. Chapter 2 discusses the structural basis of Hsp90 function, an area that has been the subject of numerous previous reviews. How- ever, it is an essential addition to the overall make-up of the book and is very well written. Chapter 3 is a beautifully written, wide-ranging review of the Hsp70 chaperone, which has been under-reviewed in comparison with Hsp90. Despite a self-professed shallow- level review, the authors have produced an outstanding overview of the subject that will be an extremely useful account for a wide variety of scientists. I learned a lot from this chapter as it is an area with which I am less familiar than Hsp90 research. Chapter 4 goes on to outline how the dependency of cancer cells on molecular chaperones can be exploited for therapeutics. This is an area in which Workman and co-workers have written extensively and authoritatively to date. Whilst some of the most recent developments are missing, including research to minimise benzoquinone ansamycin toxicity and withdrawal of IPI-504 from the clinic, the authors present an excellent and thought-provoking outlook on the future of the subject. Chapters 5-9 present the discovery and development of several Hsp90 inhibitors in the clinic. More discussion of the syntheses of the drug candidates (such as in Chapter 7) would have increased the appeal to a wider audience. Chapter 10 presents a well-written and comprehensive account of the state-of-the art in Hsp90 C terminus inhibition with an excellent summary of the findings from structure-activity relationship studies of the various inhibitors. This is also an area that has been under-researched relative to Hsp90 N-terminal inhibitors and should provoke much interest in the near future. Chapter 11 is an important summary of the state-of-the art in small- molecule Hsp70 inhibition, another up- coming research area that is sure to receive significantly more research focus looking ahead. Chapter 12 is a short account of the post-translational regulation from, amongst others, Len Neckers-another `juggernaut' of the molecular chaperone field. The discussion is thought-provoking and concise and is aided by numerous vibrant and informative figures. Chapter 13 is a detailed analysis of those Hsp90 inhibitors that have progressed to clinical trials. Although this is a section that has been extensively reviewed previously, the chapter provides a nice, comprehensive summary with a well-written outlook and is an essential addition to the book. However, it contains a disappointing number of errors including the structure of IPI-504 (it is the hydrochloride salt, not the free base as shown). The final two chapters discuss the targeting of molecular chaperones as therapeutics for important diseases such as malaria and neurological conditions. This is an invaluable addition to the book and, in addition to the Hsp70 discussion, really sets this text apart from the numerous previous review articles and books in the area. On a more critical note, the book be- comes somewhat repetitive in several places and so perhaps more distinction between the chapters could have been achieved. Another slight criticism of the book would be that whilst the majority of chapters have useful, informative figures, a small number of chapters are somewhat lacking in suitable diagrams, particularly chemical structures that would aid the discussion and increase the appeal to chemists. Additionally, in a few chapters the diagrams and structures are rather poor quality (e.g., grainy or squashed), and the chemical structures are formatted inconsistently throughout the book, with some bond angles appearing to have been drawn somewhat haphazardly. Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham * Chemmedchem review in March 2015 issue PART 1 *

...this 422- page volume adds greatly to the discussion by reporting many of the more recent advances in targeting Hsp90, whilst including an elegant overview of the advances in Hsp70 research, an area that has received considerably less re- search attention until more recently. The editors have assembled work from a variety of leading experts in the molecular chaperone field... ...the authors have produced an outstanding overview of the subject that will be an extremely useful account for a wide variety of scientists... ...the authors present an excellent and thought-provoking outlook on the future of the subject Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham Chemmedchem review in March 2015 issue The final two chapters discuss the targeting of molecular chaperones as therapeutics for important diseases such as malaria and neurological conditions. This is an invaluable addition to the book and, in addition to the Hsp70 discussion, really sets this text apart from the numerous previous review articles and books in the area. On a more critical note, the book be- comes somewhat repetitive in several places and so perhaps more distinction between the chapters could have been achieved. Another slight criticism of the book would be that whilst the majority of chapters have useful, informative figures, a small number of chapters are somewhat lacking in suitable diagrams, particularly chemical structures that would aid the discussion and increase the appeal to chemists. Additionally, in a few chapters the diagrams and structures are rather poor quality (e.g., grainy or squashed), and the chemical structures are formatted inconsistently throughout the book, with some bond angles appearing to have been drawn somewhat haphazardly. Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham Chemmedchem review in March 2015 issue PART 2 Since the discovery in the mid-1990s that geldanamycin, a benzo- quinone ansamcin, acts as an inhibitor of heat shock protein 90 (Hsp90), research in this area has boomed. Whilst several topics touched upon in this book have been extensively reviewed to date, this 422- page volume adds greatly to the discussion by reporting many of the more recent advances in targeting Hsp90, whilst including an elegant overview of the advances in Hsp70 research, an area that has received considerably less re- search attention until more recently. The editors have assembled work from a variety of leading experts in the molecular chaperone field to outline the strategies and therapeutic advances in targeting chaperone proteins to combat high-pro- file diseases, predominantly within oncology but also the less researched ap- plication to the treatment of malaria and neurodegenerative diseases. Whilst the book includes details that will provoke interest for those new to the molecular chaperone arena, the majority of the chapters involve in-depth discussion and analysis more suited to experts in the subject. Chapter 1 presents a well-written over- view of molecular chaperones, although it would benefit from some molecular structures to illustrate what is otherwise a very nice analysis of various small-molecule chaperone inhibitors. Chapter 2 discusses the structural basis of Hsp90 function, an area that has been the subject of numerous previous reviews. How- ever, it is an essential addition to the overall make-up of the book and is very well written. Chapter 3 is a beautifully written, wide-ranging review of the Hsp70 chaperone, which has been under-reviewed in comparison with Hsp90. Despite a self-professed shallow- level review, the authors have produced an outstanding overview of the subject that will be an extremely useful account for a wide variety of scientists. I learned a lot from this chapter as it is an area with which I am less familiar than Hsp90 research. Chapter 4 goes on to outline how the dependency of cancer cells on molecular chaperones can be exploited for therapeutics. This is an area in which Workman and co-workers have written extensively and authoritatively to date. Whilst some of the most recent developments are missing, including research to minimise benzoquinone ansamycin toxicity and withdrawal of IPI-504 from the clinic, the authors present an excellent and thought-provoking outlook on the future of the subject. Chapters 5-9 present the discovery and development of several Hsp90 inhibitors in the clinic. More discussion of the syntheses of the drug candidates (such as in Chapter 7) would have increased the appeal to a wider audience. Chapter 10 presents a well-written and comprehensive account of the state-of-the art in Hsp90 C terminus inhibition with an excellent summary of the findings from structure-activity relationship studies of the various inhibitors. This is also an area that has been under-researched relative to Hsp90 N-terminal inhibitors and should provoke much interest in the near future. Chapter 11 is an important summary of the state-of-the art in small- molecule Hsp70 inhibition, another up- coming research area that is sure to receive significantly more research focus looking ahead. Chapter 12 is a short account of the post-translational regulation from, amongst others, Len Neckers-another 'juggernaut' of the molecular chaperone field. The discussion is thought-provoking and concise and is aided by numerous vibrant and informative figures. Chapter 13 is a detailed analysis of those Hsp90 inhibitors that have progressed to clinical trials. Although this is a section that has been extensively reviewed previously, the chapter provides a nice, comprehensive summary with a well-written outlook and is an essential addition to the book. However, it contains a disappointing number of errors including the structure of IPI-504 (it is the hydrochloride salt, not the free base as shown). The final two chapters discuss the targeting of molecular chaperones as therapeutics for important diseases such as malaria and neurological conditions. This is an invaluable addition to the book and, in addition to the Hsp70 discussion, really sets this text apart from the numerous previous review articles and books in the area. On a more critical note, the book be- comes somewhat repetitive in several places and so perhaps more distinction between the chapters could have been achieved. Another slight criticism of the book would be that whilst the majority of chapters have useful, informative figures, a small number of chapters are somewhat lacking in suitable diagrams, particularly chemical structures that would aid the discussion and increase the appeal to chemists. Additionally, in a few chapters the diagrams and structures are rather poor quality (e.g., grainy or squashed), and the chemical structures are formatted inconsistently throughout the book, with some bond angles appearing to have been drawn somewhat haphazardly. Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham Chemmedchem review in March 2015 issue PART 1

Since the discovery in the mid-1990s that geldanamycin, a benzo- quinone ansamcin, acts as an inhibitor of heat shock protein 90 (Hsp90), research in this area has boomed. Whilst several topics touched upon in this book have been extensively reviewed to date, this 422- page volume adds greatly to the discussion by reporting many of the more recent advances in targeting Hsp90, whilst including an elegant overview of the advances in Hsp70 research, an area that has received considerably less re- search attention until more recently. The editors have assembled work from a variety of leading experts in the molecular chaperone field to outline the strategies and therapeutic advances in targeting chaperone proteins to combat high-pro- file diseases, predominantly within oncology but also the less researched ap- plication to the treatment of malaria and neurodegenerative diseases. Whilst the book includes details that will provoke interest for those new to the molecular chaperone arena, the majority of the chapters involve in-depth discussion and analysis more suited to experts in the subject. Chapter 1 presents a well-written over- view of molecular chaperones, although it would benefit from some molecular structures to illustrate what is otherwise a very nice analysis of various small-molecule chaperone inhibitors. Chapter 2 discusses the structural basis of Hsp90 function, an area that has been the subject of numerous previous reviews. How- ever, it is an essential addition to the overall make-up of the book and is very well written. Chapter 3 is a beautifully written, wide-ranging review of the Hsp70 chaperone, which has been under-reviewed in comparison with Hsp90. Despite a self-professed shallow- level review, the authors have produced an outstanding overview of the subject that will be an extremely useful account for a wide variety of scientists. I learned a lot from this chapter as it is an area with which I am less familiar than Hsp90 research. Chapter 4 goes on to outline how the dependency of cancer cells on molecular chaperones can be exploited for therapeutics. This is an area in which Workman and co-workers have written extensively and authoritatively to date. Whilst some of the most recent developments are missing, including research to minimise benzoquinone ansamycin toxicity and withdrawal of IPI-504 from the clinic, the authors present an excellent and thought-provoking outlook on the future of the subject. Chapters 5-9 present the discovery and development of several Hsp90 inhibitors in the clinic. More discussion of the syntheses of the drug candidates (such as in Chapter 7) would have increased the appeal to a wider audience. Chapter 10 presents a well-written and comprehensive account of the state-of-the art in Hsp90 C terminus inhibition with an excellent summary of the findings from structure-activity relationship studies of the various inhibitors. This is also an area that has been under-researched relative to Hsp90 N-terminal inhibitors and should provoke much interest in the near future. Chapter 11 is an important summary of the state-of-the art in small- molecule Hsp70 inhibition, another up- coming research area that is sure to receive significantly more research focus looking ahead. Chapter 12 is a short account of the post-translational regulation from, amongst others, Len Neckers-another 'juggernaut' of the molecular chaperone field. The discussion is thought-provoking and concise and is aided by numerous vibrant and informative figures. Chapter 13 is a detailed analysis of those Hsp90 inhibitors that have progressed to clinical trials. Although this is a section that has been extensively reviewed previously, the chapter provides a nice, comprehensive summary with a well-written outlook and is an essential addition to the book. However, it contains a disappointing number of errors including the structure of IPI-504 (it is the hydrochloride salt, not the free base as shown). The final two chapters discuss the targeting of molecular chaperones as therapeutics for important diseases such as malaria and neurological conditions. This is an invaluable addition to the book and, in addition to the Hsp70 discussion, really sets this text apart from the numerous previous review articles and books in the area. On a more critical note, the book be- comes somewhat repetitive in several places and so perhaps more distinction between the chapters could have been achieved. Another slight criticism of the book would be that whilst the majority of chapters have useful, informative figures, a small number of chapters are somewhat lacking in suitable diagrams, particularly chemical structures that would aid the discussion and increase the appeal to chemists. Additionally, in a few chapters the diagrams and structures are rather poor quality (e.g., grainy or squashed), and the chemical structures are formatted inconsistently throughout the book, with some bond angles appearing to have been drawn somewhat haphazardly. Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham * Chemmedchem review in March 2015 issue PART 1 * ...this 422- page volume adds greatly to the discussion by reporting many of the more recent advances in targeting Hsp90, whilst including an elegant overview of the advances in Hsp70 research, an area that has received considerably less re- search attention until more recently. The editors have assembled work from a variety of leading experts in the molecular chaperone field... ...the authors have produced an outstanding overview of the subject that will be an extremely useful account for a wide variety of scientists... ...the authors present an excellent and thought-provoking outlook on the future of the subject Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham * Chemmedchem review in March 2015 issue * The final two chapters discuss the targeting of molecular chaperones as therapeutics for important diseases such as malaria and neurological conditions. This is an invaluable addition to the book and, in addition to the Hsp70 discussion, really sets this text apart from the numerous previous review articles and books in the area. On a more critical note, the book be- comes somewhat repetitive in several places and so perhaps more distinction between the chapters could have been achieved. Another slight criticism of the book would be that whilst the majority of chapters have useful, informative figures, a small number of chapters are somewhat lacking in suitable diagrams, particularly chemical structures that would aid the discussion and increase the appeal to chemists. Additionally, in a few chapters the diagrams and structures are rather poor quality (e.g., grainy or squashed), and the chemical structures are formatted inconsistently throughout the book, with some bond angles appearing to have been drawn somewhat haphazardly. Overall the book is very well written, should appeal to academic and industrial medicinal chemists and to those in closely related fields. The text will prove particularly useful to those of a more biological persuasion or those looking to study Hsp70, and would be an excellent addition to any science or medical-based library. -- Dr. Russell R. A. Kitson, University of Nottingham * Chemmedchem review in March 2015 issue PART 2 *

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