Abstract
This book was written by a medicinal chemist in the pharmaceutical industry and the 23 chapters were written primarily by pharmacologists and chemists. It is important to read the preface in order to understand what the editor means by “polypharmacology” which he describes as “the activity of compounds at multiple targets.” While most toxicologists would refer to this phenomenon as off-target toxicity, the book looks both at this type of polypharmacology and at compounds that bind to multiple targets that may have improved safety. In other words, the book is part toxicology summary and part a call to develop multitargeted compounds. The preface also outlines the structure of the book which is helpful to the reader.
The book is divided into 4 parts. The first part of the book consists of an opening chapter which presents the rationale for multitargeted compounds followed by chapters discussing the side effects associated with off-target binding and ways to screen for these early in the discovery process. This reviewer is surprised that this type of screening is not routine in the pharmaceutical industry as it certainly can explain the types of toxicities seen during both preclinical and clinical drug development. In addition to a listing of a variety of products which have been withdrawn from market due to “unexpected” side effects, this section of the book also presents data on various properties of compounds that contribute to multiple binding such as lipophilicity, molecular weight, and ionization potential. A chapter on kinases as antitargets in genotoxicity presents a succinct overview of the subject. There is a detailed table showing the various cyclin-dependent kinases and where they act during cell division. A following chapter is a summary of activity at cardiovascular ion channels. While this chapter is quite basic in its review of patch clamping technique and the discussion of compounds that block the channels, there is a good presentation of medicinal chemistry approaches to decrease hERG (human Ether-á-go-go Related Gene) channel blockage.
The second part of the book takes the reader through a variety of diseases where compounds with multiple targets may be of use. Psychiatric diseases, cancer, bacterial infections, and epilepsy are all discussed in their own chapters. The chapter on psychiatric diseases lists a summary of compounds from the PubChem databases and the number of molecular targets at which they are active. Compounds ranged from activity at 0 target to 59 targets. While this is interesting, it would have been more helpful to show whether these targets are helpful or hurtful in controlling the disease state for which they are prescribed. The chapter on cancer does a better job of presenting various kinase inhibitors and their multiple targets. Each compound is discussed in some detail as to how it was designed and tested and its stage of development.
The third part of the book includes chapters on a series of methods presenting in vitro, in vivo, and in silico approaches to identify compounds with polypharmacologic properties. The approaches include the use of medicinal chemistry to synthesize a family of compounds to determine the activity at various receptor sites, using computational chemistry tools such as automated binding site identification and docking of compounds with targets, in vitro screening in receptor assays, and the use of in vivo high-throughput screening.
The last portion of the book presents case histories of various polypharmacology drugs and how they were discovered and developed. Various cancer compounds such as nilotinib and sunitinib are discussed from molecule design through development and approval. Chapters discussing disease states where drugs have not been approved present ongoing efforts to develop multitargeted drugs. A chapter on the development of triple-uptake inhibitors as antidepressants shows a good case history from the theory behind the compounds through a presentation of the preclinical data followed by the clinical data. While this approach seems reasonable in theory, the clinical trials to date have not shown efficacy.
Each chapter is cogently presented with most of the chapters reading like a stand-alone journal article. The book is filled with excellent figures and graphs, including 8 full color pages which are lovely but placed in the middle of the book rather than with each chapter, requiring the reader to flip back and forth while reading the chapters associated with these pictures. The author list fails to give the degrees or the positions held of the 53 authors, forcing the reader to turn to the Internet to find out more about each one in cases where the experience of an author may be of interest. The author affiliations are listed separately rather than with each chapter, creating some work for the reader to determine information about them.
This book may be useful for pharmaceutical discovery people in small companies where “polypharmacology” is not part of the discovery/development process. It may also be of interest to entry level pharmaceutical development personnel as an overview of the off-target toxicity of withdrawn compounds, factors leading to off-target binding and as a blueprint for the development of polypharmacological compounds. Medicinal chemists will certainly find interesting the story of what happens to compounds after they leave the preclinical arena.
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