1. Young, Robert C. MD

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Some of you may notice that the last names of the author of The Quest for the Cure and the Editor of Oncology Times are the same. This is not a coincidence-they are mother and son. This says more about how this reviewer came to discover the book than about any nepotism that might be implied.

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REVIEWED BY ROBERT C... - Click to enlarge in new windowREVIEWED BY ROBERT C. YOUNG, MD, Chairman,

Indeed, I might never have seen or read the book, because the title, The Quest for the Cure, suggests it might be one of the hundreds of "medical cure" volumes pouring on to the market each year. A quick perusal of a popular website finds more than 500 books on medical or cancer cures, most of them natural cures, conspiracy theories, dietary strategies, and the like. Although Stockwell's book's title suggests a sweeping exploration of the causes and treatments of medical illness, it is rather a focused effort to address one of the critical obstacles facing drug development today.


While one can sympathize with Dr. Stockwell, who mentions in the acknowledgements that his sons helped select the title, the subtitle-"The Science and Stories behind the Next Generation of Medicines-is actually a better description of the book's focus.


Just to be clear, this is no self-help work for the pulp market, but rather a serious, well-crafted, and illuminating analysis of one of medicine's great challenges-"undruggable" protein targets that have resisted treatment to date.


The first section of the book reviews the basics of drug development and highlights some of the historical and more modern triumphs in the development of modern medicines. Stockwell explores many of the classical drug discovery stories from the vantage point of a chemist, which brought, at least to this reader, a fresh and not commonly encountered perspective.


The author, a molecular biologist and chemist at Columbia University and a Howard Hughes Medical Institute Early Career Scientist, deftly and clearly explains the mechanisms of drug/target interactions and points out that in spite of the progress, less than two percent of human cellular proteins have been targeted and fewer than 15 percent are even considered druggable.


Indeed all of the known drugs target fewer than 425 human proteins. Of the 20,500 proteins encoded in the human genome, there are felt to be only between 200 and 500 that are druggable.


Many drug discovery scientists have grown to believe that most proteins are simply not capable of binding in a selective way to small molecules that can become drugs. Stockwell notes that about half of the 400 or so druggable proteins fall into just five families: kinases, proteases, nuclear hormone receptors, phosphodiesterases, and G-protein-coupled receptors. Thus, like the drunk looking for his keys under the streetlight, we continue to focus on the few families of druggable proteins and neglect the others.


It is the assumption that the large body of undruggable proteins are not targetable that Dr. Stockwell addresses in the second half of the book. He notes that many major protein families such as kinases, proteases, hormone receptors, and others were once thought to be undruggable. His examples of evolving technology, which allows wider drug targeting reminds one of the old adage from Pliny the Elder: "How many things too are looked on as quite impossible until they have been actually effected."


In exploring the path to the next generation of medicines, Stockwell's scientific expertise really shines. He illustrates how x-ray crystallography and nuclear magnetic resonance can be used to define three-dimensional shapes of complex proteins to identify potential target sites. He explains structure-activity based drug design, fragment-based drug development, and in silico-based drug screening, where parallel computing allows the investigator to test the ability of millions of different small molecules to interact with dozens of different potential target proteins.


These illuminating but challenging chapters are not for the faint of heart and they address complex and evolving new technology. To reiterate a quote that Stockwell uses from Einstein-"Things should be made as simple as possible but no simpler."


He returns throughout the book to the vexing problem of the yet undruggable RAS proteins, and while solutions are not yet at hand, leaves the reader with the understanding that multipronged options are being explored and eventual solutions are likely to be forthcoming.


For instance, he points out that just about all of the 85 percent of undruggable proteins engage in protein-protein interactions and if one could block those interactions one could control signaling mechanisms. He guides the reader through the complex maze of the emerging science of protein transduction peptides, foldamers, miniproteins, and stapled proteins, which may be used to produce designer biologics to solve the intractable problems of undruggable proteins. It is impossible to read this relatively short book (228 pages, not counting the notes and index) without being captured by the author's optimism about the future of drug development.


The Quest for the Cure is more for the medical scientist and clinician than for a lay audience. Although he writes clearly, the subjects are complex and the science involved might seem both intimidating and hyper-focused to the lay reader.


Oncologists however will recognize that unraveling the mysteries surrounding the undruggable proteins is at the heart of future progress in cancer treatment. Dr. Stockwell left me with the feeling that we will eventually get there.