Fragment-based drug discovery

313 Pages·2014·22.151 MB·English

Fragment-Based Drug Discovery
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RSC Drug Discovery Series
Editor-in-Chief
Professor David Thurston, King’s College, London, UK
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0 Series Editors:
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F Professor David Rotella, Montclair State University, USA
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93 Professor Ana Martinez, Centro de Investigaciones Biologicas-CSIC,
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62 Madrid, Spain
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78 Dr David Fox, Vulpine Science and Learning, UK
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9/ Advisor to the Board:
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1 Professor Robin Ganellin, University College London, UK
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g | d Titles in the Series:
or 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
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s.rs 2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
ub 3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
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p:// 4: Accounts in Drug Discovery
htt 5: New Frontiers in Chemical Biology
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o 6: Animal Models for Neurodegenerative Disease
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01 7: Neurodegeneration
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8:20:46. 17 June 89:: GPh Parromteaicne-uCtoicuapll Pedro Rceecsse pDteovreslopment
0n 10: Extracellular and Intracellular Signaling
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d 11: New Synthetic Technologies in Medicinal Chemistry
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blis 12: New Horizons in Predictive Toxicology
u 13: Drug Design Strategies: Quantitative Approaches
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14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques and Applications
21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials for Overcoming Biological Barriers
23: Physico-Chemical and Computational Approaches to Drug Discovery
24: Biomarkers for Traumatic Brain Injury
25: Drug Discovery from Natural Products
26: Anti-Inflammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric Disorders
29: Organic Chemistry of Drug Degradation
30: Computational Approaches to Nuclear Receptors
31: Traditional Chinese Medicine
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32: Successful Strategies for the Discovery of Antiviral Drugs
33: Comprehensive Biomarker Discovery and Validation for Clinical
Application
34: Emerging Drugs and Targets for Parkinson’s Disease
35: Pain Therapeutics; Current and Future Treatment Paradigms
01 36: Biotherapeutics: Recent Developments using Chemical and Molecular
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FP Biology
38- 37: Inhibitors of Molecular Chaperones as Therapeutic Agents
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20 38: Orphan Drugs and Rare Diseases
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82 39: Ion Channel Drug Discovery
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81 40: Macrocycles in Drug Discovery
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9/9 41: Human-based Systems for Translational Research
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0 42: Venoms to Drugs: Venom as a Source for the Development of Human
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10. Therapeutics
doi: 43: Carbohydrates in Drug Design and Discovery
g | 44: Drug Discovery for Schizophrenia
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c. 45: Cardiovascular and Metabolic Disease: Scientific Discoveries and New
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s.r Therapies
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p 46: Green Chemistry Strategies for Drug Discovery
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Fragment-Based Drug
Discovery
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81 Steven Howard
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9/9 Astex Pharmaceuticals, Cambridge, UK
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doi: Chris Abell
org | Department of Chemistry, University of Cambridge, UK
c. Email: [email protected]
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or RSC Drug Discovery Series No. 47
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bs.r Print ISBN: 978-1-84973-908-5
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http://p PISDSFN e: I2S0B4N1-:3 927083-1-78262-093-8
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e Apart from fair dealing for the purposes of research for non-commercial purposes or for
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8- Foreword
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10 In 1995 Glaxo Wellcome acquired Affymax, the pioneering Combinato-
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1 rial Chemistry company based in California, for ∼$500m in an attempt to
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d increase the productivity of its research. The 1990s was a decade in which
org | many industry executives believed that in order to increase the output of
sc. their R&D groups ‘industrialisation’ of the whole process was required. As
bs.r such, significant investment was made in infrastructure for high-throughput
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p:// screening and combinatorial synthesis in most major pharmaceutical com-
htt panies. The belief was that the ability to rapidly screen libraries of several
on 100,000 compounds against key disease targets would yield many new drugs.
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1 Combinatorial chemistry was an approach to generate those huge com-
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08:2n 17 drug discovery. Despite the initial promise and the huge increase in apparent
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d productivity, we soon came to realise that many lead compounds discovered
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sh using these approaches did not have optimal physico-chemical properties
ubli that would allow them to be developed into high-quality drug candidates.
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The subsequent years have shown that our initial concerns were valid as this
approach of industrialising drug discovery has largely failed. It is clear that
drug discovery is a personal endeavour, not a process.
One of the goals of screening huge combinatorial chemistry libraries was
an attempt to increase the area of chemical space that was being sampled.
Compounds in these early libraries were typically large (MW > 350 Da) as
they contained multiple functional groups to increase the chance of finding
interactions with the protein target. An alternative, and at the time contrar-
ian, approach to crack this same nut was to consider screening compounds
that were much smaller and which contained perhaps only one functional
group. The potential advantage of this approach was that the functional
group would not be sterically hindered; as in the case where it was part of
RSC Drug Discovery Series No. 47
Fragment-Based Drug Discovery
Edited by Steven Howard and Chris Abell
© The Royal Society of Chemistry 2015
Published by the Royal Society of Chemistry, www.rsc.org
vii
View Online
viii Foreword
a larger molecule. However, the initial binding affinity against the target
would be rather low, perhaps mM, which would pose significant challenges
in detection. It turned out that there was an even bigger challenge; the cul-
tural shift required in the minds of medicinal chemists to appreciate such a
low-affinity starting point. There were many conversations in the early years
07 during which this point was made; it was already difficult enough to optimise
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FP a µM hit from an HTS campaign, why would anyone consider starting with a
38- mM fragment hit! Of course in those years many scientists continued to be
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20 seduced by ligand potency, not ligand efficiency.
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82 As is now generally accepted, the fragment discovery approach is a de-
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81 convolution of the combinatorial methodology and should allow the same
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9/9 (or even more) chemical space to be sampled using significantly smaller
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0 numbers of compounds. Indeed, a library of 1000 fragments can be shown
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10. to represent a similar (or even greater) range of chemical space, when com-
doi: pared with a combinatorial library of 1 000 000 larger compounds. Therefore,
g | the fragment approach is a more elegant and perhaps more intellectually sat-
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c. isfying approach which could explain why not only industrial groups but also
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s.r academic groups have embraced it. A key challenge in fragment screening is
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http:// 5–10 mM range in the case of protein–protein systems, and then of course to
n develop those fragment hits into useful drug leads. However, many groups
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15 over the years have successfully overcome these challenges as highlighted by
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8:217 now established as one of the many technologies utilised by pharmaceutical
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blis Dr Harren Jhoti
Pu President and CEO
Astex Pharmaceuticals
Cambridge, UK
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8- Preface
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10 Since the seminal work by Fesik et al. ‘SAR by NMR’ in 1996, fragment-based
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1 drug discovery (FBDD) has become an established technique within both the
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d pharmaceutical industry and academia. The concept is simple; that is small
org | molecules, or fragments (MW < 300 Da), are more likely to form a specific com-
sc. plex with a given protein, than are larger molecules. A consequence of this is
bs.r that chemical space can be sampled much more efficiently using fragments
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p:// than using molecules of greater complexity. Fragment-based screening, and
htt successive optimisation of hits towards lead molecules, has been applied to
on many different protein targets across a variety of therapeutic areas. The first
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1 fragment-derived drug, vemurafenib, an inhibitor of mutant B-RAF (for treat-
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08:2n 17 This book aims to ‘take stock’ of the latest advances in the field of FBDD. In
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sh and academia describe the latest techniques and applications. The authors
ubli lay out case studies, critical review and opinions which will give the reader a
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thorough appreciation of both the principles and best practice within FBDD.
One consequence of screening smaller, simpler fragments is that their
binding affinity is often relatively low (>1 mM). Developing assays of suffi-
cient sensitivity, and fidelity, to identify fragments with low binding affinity
has been a fundamental challenge of FBDD. As necessity is the mother of
invention, this challenge has driven the development of highly sophisticated
biophysical screening techniques based on X-ray protein crystallography,
surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR).
SPR and NMR are covered in detail by Tony Giannetti and Isabelle Krimm in
Chapters 2 and 3, respectively. X-ray protein crystallography features heav-
ily in most chapters, both in a screening role and in support of structure-
based fragment evolution. Comparing and contrasting the output from these
RSC Drug Discovery Series No. 47
Fragment-Based Drug Discovery
Edited by Steven Howard and Chris Abell
© The Royal Society of Chemistry 2015
Published by the Royal Society of Chemistry, www.rsc.org
ix
View Online
x Preface
biophysical screening techniques is an area of active debate. This is discussed
by Ian Wall et al. in Chapter 4.
FBDD continues to evolve rapidly and has recently seen new applications
in areas such as epigenetics, G protein-coupled receptors (GPCRs), protein–
protein interactions, antibacterials and the identification of novel allosteric
09 binding pockets. In this book, experts from each of these fields discuss les-
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FP sons learned based on both their own experience and key examples from
38- the literature. These chapters describe aspects of fragment library design,
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20 screening techniques and hit validation. Examples include strategies for
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82 optimisation of fragments towards lead compounds, and, ultimately, drug
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81 candidates.
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9/9 We would like to thank all the contributors to the chapters in this book for
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0 their outstanding effort and commitment to this project. We would also like
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10. to thank the staff at the RSC for their support in bringing this book to com-
doi: pletion. We hope that this book will provide a useful resource for scientists
g | who are looking to understand the practice of FBDD.
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s.rs Steven Howard
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u Department of Medicinal Chemistry
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p:// Astex Pharmaceuticals
htt Cambridge, UK
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15 Chris Abell
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