The advancement of our understanding of the cellular functions of molecular chaperones in both normal and diseased states has come a long way. Since the first coinage of the term “molecular chaperone” by Laskey in 19781 to the present day, tremendous progress has been made in elucidating the structure and function of this important class of proteins and has resulted in the pursuit of inhibitors to address major unmet medical needs such as cancer and neurodegenerative diseases.
Molecular chaperones play a significant role in maintaining and adjusting protein homeostasis. They assist in the folding, maturation, and stabilization of a host of client proteins involved in health and disease. An ideal target from a drug discovery perspective is one that is essential for a diseased state but non-essential for the normal, healthy state. How the molecular chaperones, which play such an important role in normal cell function, can be useful as therapeutic targets is still the subject of some controversy but the evidence is mounting that clinical success is achievable.
The goal of this book is to provide a comprehensive examination of the field of molecular chaperones, their modulation, and application to pharmaceutical research. With over 10 small molecule Hsp90 inhibitors currently in oncology clinical development, we have accumulated significant knowledge in basic drug discovery as well as in clinical translational research for drugging molecular chaperones. With the ever increasing difficulty of bringing new therapies to market, it is imperative that we apply these collective experiences to future drug discovery efforts to improve our chances for success. It is our hope that researchers both in the field of molecular chaperones and in drug discovery will find this retrospective analysis and forward-looking concepts from bench to bedside valuable.
Written by top experts from both academia and industry, this volume brings together for the first time the current knowledge of basic structure and function of molecular chaperones, the design and development of several small molecule inhibitors, and the application of these inhibitors in clinical settings.
Section I serves as background and introduction to molecular chaperones and their associated biology and contributions to human diseases. Chapter 1 provides a comprehensive review of the many types of molecular chaperones and presents their connections with diseases and the phenotypes of genetic alterations of the genes encoding them. An overview of strategies that have been developed to modulate the activity of several molecular chaperones is also presented. The structure and function of two of the most studied molecular chaperones, Hsp90 and Hsp70 are detailed in chapter 2 and chapter 3. Chapter 4 demonstrates how the dependency of cancer cells on molecular chaperones, such as Hsp90, can be exploited to provide potential therapies for this important disease area.
Section II provides detailed case studies of the academic and industrial discovery efforts of several small molecule inhibitors. Chapters 5 through 9 detail the drug discovery leading to several inhibitors of the N-terminal domain of Hsp90 in clinical development. Chapter 10 describes preclinical development of inhibitors of the C-terminal domain of Hsp90. Chapter 11 presents an overview of recent discovery of several classes of Hsp70 inhibitors.
While most of the initial effort has been in the field of oncology, recent work in other disease areas is emerging. Chapters 12 and 13 describe the current state of Hsp90 inhibitor clinical development in oncology. Chapter 14 addresses the role of Hsp90 as an antimalarial therapeutic target. Finally, Chapter 15 describes the opportunities that exist for molecular chaperones as therapeutic targets in neurodegenerative diseases.
Such a comprehensive undertaking would not have been possible without the committed diligence of the individual chapter authors. For their scholarship, scientific rigor, hard work, dedication, and patience during the lengthy process of writing, reviewing, and editing their contributions, we are grateful.
Timothy D. Machajewski