Fragment-Based Drug Discovery: Lessons and Outlook

In 2006, Wolfgang Jahnke and I co-edited the very first book on fragment-based drug discovery. Half a dozen books have followed, most of which have been reviewed at Practical Fragments (see right-hand column). These are now joined by a new book edited by Wolfgang and me in Wiley’s Methods and Principles in Medicinal Chemistry series.

At 500 pages and 19 chapters, this is the most extensive treatment since the Methods in Enzymology volume five years ago. In the interest of space I can’t write more than a sentence or two about each chapter, but I would like to thank all the contributors. Although I’m undoubtedly biased, I believe this work will set the standard for years to come.

The book is divided into three sections, starting with The Concept of FBDD. Rod Hubbard (Vernalis and University of York) opens with a chapter on the role of FBDD in lead-finding, which provides an introduction, historical overview, and summary of current thinking and future challenges. One particularly interesting section compares the contents of the 2006 book with the state of the art today, highlighting the fact that many of the basic techniques were already in place a decade ago, but the number of success stories has increased dramatically.

Chapter 2, by Glyn Williams and colleagues at Astex, discusses how to choose targets for FBDD, including concepts such as ligandability. Key principles are nicely illustrated with several important targets including the IAPs and HCV-NS3.

The last two chapters in this section focus more on numbers. Chapter 3, by Jean-Louis Reymond and colleagues at the University of Berne, covers the computational enumeration of chemical space, with a special emphasis on the contents and uses of their GDB-17 set of the 166 billion possible molecules with up to 17 non-hydrogen atoms. And chapter 4, by György Ferenczy and György Keseű at the Hungarian National Academy of Sciences, provides an overview of various metrics (such as ligand efficiency and LELP) and how these can be useful for fragment optimization.

The next nine chapters comprise the longest sub-section of the book, Methods and approaches for FBDD. To start screening fragments, you need a library, and designing one is the subject of chapter 5, by Martin Drysdale and colleagues at the Beatson Institute. This chapter also touches on concepts such as molecular complexity and “three-dimensional” fragments.

Screening techniques are best used in combination, and in chapter 6 Ben Davis (Vernalis) and Tony Giannetti (Google[x]) describe the synthesis of results from SPR, NMR, X-ray, ITC, functional screens, and other techniques to overcome challenges in several discovery programs. They emphasize that universal agreement among different methods is not always necessary, but carefully analyzing discrepancies can reveal unexpected problems with the screening conditions, target, or hits.

Differential scanning fluorimetry (DSF) – or thermal shift (TS) – is perhaps the most controversial screening method, and in chapter 7 Chris Abell and colleagues at the University of Cambridge cover this approach in depth. The chapter starts with a thermodynamically detailed yet nonetheless lucid discussion of the theory behind DSF, including the interpretation of negative thermal shifts. The chapter also includes plenty of practical advice and case studies, some of which we’ve covered briefly (for example here and here).

Chapter 8, by Sten Ohlson and Minh-Dao Duong-Thi at Nanyang Technological University, covers three emerging fragment screening technologies: WAC, native MS, and MST. And Chapter 9, by Sandor Vajda (Boston University) and collaborators, does an excellent job of summarizing computational approaches.

As others have noted, some of the biggest challenges are not technical but organizational, and in chapter 10 Michelle Arkin and colleagues at UCSF describe how to make FBDD work in academia. The chapter also includes some interesting polling data, concise but cogent summaries of fragment-finding techniques, and case studies on p97 and caspase-6. And in chapter 11, Jim Wells and colleagues – also at UCSF – describe using Tethering to find allosteric sites in proteins.

One area that has grown dramatically since 2006 is the use of FBDD in complex systems (such as membrane proteins), the subject of a chapter by Miles Congreve and John Christopher at Heptares. Chapter 12 also includes successful case studies, some of which we’ve covered. But finding fragments against these targets is still not easy, as illustrated in the final figure: of 18 fragment hits on 15 targets, almost all have ligand efficiency values > 0.3 kcal/mol per atom, and most of them are relatively potent, with affinities in the mid-micromolar range or better. While everyone wants to find strong binders from the start, such numbers suggest many weak-binding hits are overlooked.

Chapter 13, by Jörg Rademann and colleagues at Freie Universität Berlin, covers protein-templated fragment ligation methods, both reversible and irreversible. The chapter is wide-ranging and includes methods such as dynamic libraries and various types of “Click” chemistries.

The last section of the book, which was mostly absent a decade ago, is entitled Successes from FBDD. This starts with a chapter by Daniel Wyss, Andrew Stamford, and colleagues from Merck on BACE inhibitors. As we’ve noted, fragments have had a major role in most of the BACE inhibitors to enter the clinic, with phase III results from Merck’s verubecestat expected next year.

Epigenetics has also been strongly influenced by fragments, and in chapter 15 Aman Iqbal (Proteorex) and Peter Brown (Structural Genomics Consortium) survey the field, with case studies on several proteins that modulate epigenetic marks. These include BRD4, ATAD2, BAZ2B, SIRT2, and others.

One of the original selling points of fragment-based methods is the ability to go after difficult targets such as protein-protein interactions, and this is the subject of chapter 16, by Feng Wang and Stephen Fesik (Vanderbilt University). In addition to general guidelines, the researchers describe a number of case studies, including RPA, MCL-1, and K-Ras.

Some enzymes can be just as difficult as protein-protein interactions, and in chapter 17 Alexander Breeze (University of Leeds) and former AstraZeneca colleagues describe programs to find inhibitors of LDHA (see here and here). They also discuss how some previously reported inhibitors turned out to be artifacts.

More than two dozen kinase inhibitors have been approved by the US FDA, including the first drug derived from FBDD. In chapter 18, Gordon Saxty (Fidelta) surveys a number of kinase programs, including most of the fragment-derived inhibitors in clinical trials.

And finally, in chapter 19 Simon Rüdisser and colleagues from Novartis present an extensive discussion of renin, with special attention to their campaign, which involved a combination of HTS and fragment-based approaches.

While it may not be possible to judge a book by its cover, the cover of this book does illustrate some of the fruits of the field, with structures of three fragment-derived drugs that have entered the clinic. These are just a small fraction of the 30+ drugs working their way through the pipeline, and of the many more that will spring from the research described and informed by the work presented.