Inhibitors of Molecular Chaperones as Therapeutic Agents

442 Pages·2013·12.92 MB·English

by  Timothy D Machajewski, Zhenhai Gao, David Rotella, Didier Picard, Chrisostomos Prodromou, Lila Gierasch, Paul Workman, Marco Biamonte, Weiwen Ying, Tim Haystead, Michael Ruggard-Jensen, Brian Blagg, Wenlai Zhou, Len Neckers, Emin Avsar, Utpal Tatu, Pamela McLean

Inhibitors of Molecular Chaperones as Therapeutic Agents
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RSC Drug Discovery Series
Editor-in-Chief:
Professor David Thurston, King’s College, London, UK
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9- Dr David Fox, Vulpine Science and Learning, UK
68 Professor Ana Martinez, Medicinal Chemistry Institute-CSIC, Madrid, Spain
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73 Professor David Rotella, Montclair State University, USA
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7 Advisor to the Board:
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39/ Professor Robin Ganellin, University College London, UK
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oi: Titles in the Series:
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g | 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
or 2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
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s.rs 3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
ub 4: Accounts in Drug Discovery
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htt 6: Animal Models for Neurodegenerative Disease
n 7: Neurodegeneration
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13 8: G Protein-Coupled Receptors
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u 16: Pharmaceutical Salts and Cocrystals
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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
32: Successful Strategies for the Discovery of Antiviral Drugs
33: Comprehensive Biomarker Discovery and Validation for Clinical
Application
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34: Emerging Drugs and Targets for Parkinson’s Disease
35: Pain Therapeutics; Current and Future Treatment Paradigms
36: Biotherapeutics: Recent Developments using Chemical and Molecular
Biology
37: Inhibitors of Molecular Chaperones as Therapeutic Agents
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Inhibitors of Molecular
Chaperones as Therapeutic
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d o rTheRoyalSocietyofChemistry2014
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9- Preface
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10. The advancement of our understanding of the cellular functions of molecular
doi: chaperonesinbothnormalanddiseasedstateshascomealongway.Sincethe
g | first coinage of the term ‘‘molecular chaperone’’ by Laskey in 19781 to the
or
c. present day, tremendous progress has been made in elucidating the structure
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bs.r andfunctionofthisimportantclassofproteinsandhasresultedinthepursuit
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http://p orofdiengheinbeitroartsivteodaisdedarseesss. major unmet medical needs such as cancer and neu-
n Molecular chaperones play a significant role in maintaining and adjusting
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13 proteinhomeostasis.Theyassistinthefolding,maturation,andstabilizationof
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er 2 ahost ofclientproteinsinvolvedin health and disease.Anideal targetfrom a
ob drug discovery perspective is one that isessential for a diseased state but non-
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O essential for the normal, healthy state. How the molecular chaperones, which
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. n 2 playsuchanimportantroleinnormalcellfunction,canbeusefulastherapeutic
d o targetsisstillthesubjectofsomecontroversybuttheevidenceismountingthat
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h clinical success is achievable.
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ubli Thegoalofthisbookistoprovideacomprehensiveexaminationofthefield
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ofmolecularchaperones,theirmodulation,andapplicationtopharmaceutical
research. With over 10 small molecule Hsp90 inhibitors currently in oncology
clinicaldevelopment,wehaveaccumulatedsignificantknowledgeinbasicdrug
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
researchersbothinthefieldofmolecularchaperonesandindrugdiscoverywill
find this retrospective analysis and forward-looking concepts from bench to
bedside valuable.
Writtenbytopexpertsfrombothacademiaandindustry,thisvolumebrings
togetherforthefirsttimethecurrentknowledgeofbasicstructureandfunction
RSCDrugDiscoverySeriesNo.37
InhibitorsofMolecularChaperonesasTherapeuticAgents
EditedbyTimothyMachajewskiandZhenhaiGao
rTheRoyalSocietyofChemistry2014
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
vii
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viii Preface
ofmolecularchaperones,thedesignanddevelopmentofseveralsmallmolecule
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
7 provides a comprehensive review of the many types of molecular chaperones
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P0 and presents their connections with diseases and the phenotypes of genetic
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9- alterations of the genes encoding them. An overview of strategies that have
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96 beendevelopedtomodulatetheactivityofseveralmolecularchaperonesisalso
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97 presented. The structure and function of two of the most studied molecular
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18 chaperones,Hsp90andHsp70aredetailedinchapter2andchapter3.Chapter4
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97 demonstrates how the dependency of cancer cells on molecular chaperones,
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3 such as Hsp90, can be exploited to provide potential therapies for this
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oi: Section II provides detailed case studies of the academic and industrial
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g | discovery efforts of several small molecule inhibitors. Chapters 5 through 9
or detailthedrugdiscoveryleadingtoseveralinhibitorsoftheN-terminaldomain
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s.rs ofHsp90inclinicaldevelopment.Chapter10describespreclinicaldevelopment
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u of inhibitors of the C-terminal domain of Hsp90. Chapter 11 presents an
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p:// overview of recent discovery of several classes of Hsp70 inhibitors.
htt Whilemostoftheinitialefforthasbeeninthefieldofoncology,recentwork
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3 o inotherdiseaseareasisemerging.Chapters12and13describethecurrentstate
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er the role of Hsp90 as an antimalarial therapeutic target. Finally, Chapter 15
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3 targets in neurodegenerative diseases.
. n 2 Suchacomprehensiveundertakingwouldnothavebeenpossiblewithoutthe
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ed committed diligence of the individual chapter authors. For their scholarship,
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Timothy D. Machajewski
Zhenhai Gao
Reference
1. R.A.Laskey,B.M.Honda,A.D.MillsandJ.T.Finch,Nature,1978,275,
416–420.
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03 Chapter1 OverviewofMolecularChaperonesinHealthandDisease 1
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0. Tai Wang, Pablo C. Echeverrı´a and Didier Picard
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g | 1.1 Proteostasis and the Central Role of Molecular
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c. Chaperones 1
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s.r 1.2 The Major Classes of Molecular Chaperones 2
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n 1.2.3 Hsp70 and J Proteins 3
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3 1.2.4 Chaperonins 3
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2 1.2.5 Small Hsps 4
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Oct 1.4 Molecular Chaperones in Health and Disease 5
. n 23 1.5 Strategies for Modulating Chaperone Activities 10
o 1.5.1 Hsp90 Inhibitors 10
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1.5.4 Modulators of the HSF-1 Pathway 23
References 26
Chapter 2 Structural Basis of Hsp90 Function 37
Chrisostomos Prodromou and Laurence H. Pearl
2.1 Introduction 37
2.2 Domain Structure of Hsp90 38
2.3 Determining the Rate-limiting Step of the
Hsp90 Cycle 39
RSCDrugDiscoverySeriesNo.37
InhibitorsofMolecularChaperonesasTherapeuticAgents
EditedbyTimothyMachajewskiandZhenhaiGao
rTheRoyalSocietyofChemistry2014
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
ix
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x Contents
2.4 Nucleotide Interactions of the ADP and
ATP/AMP-PNP Bound States of Hsp90 40
2.5 Structural Changes in Cytosolic Hsp90 upon
ATP Binding 42
9 2.6 Structural Changes in the Middle Domain of Hsp90 44
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9 2.10 Co-chaperoneRegulationandModulationof
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81 StructuralElementsoftheHsp90ATPaseMachinery 47
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9/9 2.11 Co-chaperonesthatDeliverClientProteinstoHsp90
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10. 2.12 Co-chaperones that Activate the ATPase Activity
doi: of Hsp90 51
org | 2.13 Co-chaperones that Modulate the ATPase Activity
sc. of Hsp90 54
bs.r 2.14 Co-chaperonesthatTargetHsp90ClientProteinsfor
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p:// Proteasome Degradation 55
htt 2.15 Client Proteins and Activation of Hsp90 56
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. n 2 Chapter 3 Structure and Function of Hsp70 Molecular Chaperones 65
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d Eugenia M. Clerico and Lila M. Gierasch
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u 3.1 Introduction 65
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3.2 General Background on Hsp70 Chaperones 66
3.3 Classes of Human Hsp70s 68
3.4 Hsp70 Structure 71
3.4.1 The Hsp70 NBD 71
3.4.2 The Hsp70 Interdomain Linker 72
3.4.3 The Hsp70 SBD 73
3.4.4 Hsp70 Substrate Binding 74
3.4.5 The Disordered Hsp70 C-terminal Domain 76
3.5 Hsp70 Allosteric Mechanism 76
3.6 Co-chaperones 79
3.6.1 J proteins 79
3.6.2 NEFs 84
3.6.3 Other Co-chaperones 87
3.7 Cellular Functions of Hsp70s 89
3.7.1 De Novo Protein Folding 89
3.7.2 Protein Re-folding 90
3.7.3 Protein Degradation 91