Small-Molecule Inhibitors of Protein-Protein Interactions

180 Pages·2011·3.523 MB·English

by  Marc J. Adler, Andrew G. Jamieson (auth.), Lyubomir Vassilev, David Fry (eds.)

Current Topics in Microbiology and Immunology
Volume 348
Series Editors
Klaus Aktories
Albert-Ludwigs-Universita¨tFreiburg,Medizinische Fakulta¨t, Institutfu¨rExperimentelle
undKlinischePharmakologie undToxikologie,Abt. I,Albertstr.25, 79104Freiburg,
Germany
Richard W.Compans
EmoryUniversity Schoolof Medicine, Department ofMicrobiologyand Immunology,
3001Rollins Research Center,Atlanta, GA30322, USA
Max D.Cooper
Department of PathologyandLaboratory Medicine, GeorgiaResearch Alliance,
EmoryUniversity, 1462Clifton Road,Atlanta, GA30322, USA
Yuri Y.Gleba
ICONGenetics AG,Biozentrum Halle,Weinbergweg 22, Halle 6120,Germany
Tasuku Honjo
Department of Medical Chemistry, KyotoUniversity, Facultyof Medicine, Yoshida,
Sakyo-ku,Kyoto606-8501, Japan
Hilary Koprowski
ThomasJefferson University, Department ofCancer Biology, BiotechnologyFoundation
Laboratories, 1020Locust Street,Suite M85JAH, Philadelphia, PA 19107-6799,USA
BernardMalissen
Centre d’Immunologiede Marseille-Luminy, ParcScientifique deLuminy, Case906,
Marseille Cedex 9 13288, France
FritzMelchers
Max PlanckInstituteforInfection Biology, Charite´platz1, 10117Berlin,Germany
Michael B.A. Oldstone
ViralImmunobiologyLaboratory,Dept.ofImmunology&MicrobialScience,TheScripps
Research Institute, 10550North TorreyPines, LaJolla, CA 92037, USA
SjurOlsnes
Department of Biochemistry, InstituteforCancer Research,The Norwegian Radium
Hospital,Montebello 0310Oslo, Norway
Peter K.Vogt
TheScrippsResearchInstitute,Dept.ofMolecular&ExperimentalMedicine,10550North
TorreyPines Road.BCC-239, LaJolla, CA 92037, USA
Current Topics in Microbiology and Immunology
Previously published volumes
Further volumes can be found at springer.com
Vol.322:Romeo,Tony(Ed.): Vol.335:Levine,Beth;Yoshimori,Tamotsu;
BacterialBiofilms.2008. Deretic,Vojo(Eds.):
ISBN978-3-540-75417-6 AutophagyinInfectionandImmunity.2009.
ISBN978-3-642-00301-1
Vol.323:Tracy,Steven;Oberste,M.Steven;
Drescher,KristenM.(Eds.): Vol.336:Kielian,Tammy(Ed.):
GroupBCoxsackieviruses.2008. Toll-likeReceptors:RolesinInfectionand
ISBN978-3-540-75545-6 Neuropathology.2009.
ISBN978-3-642-00548-0
Vol.324:Nomura,Tatsuji;Watanabe,
Takeshi;Habu,Sonoko(Eds.): Vol.337:Sasakawa,Chihiro(Ed.):
HumanizedMice.2008. MolecularMechanismsofBacterialInfection
ISBN978-3-540-75646-0 viatheGut.2009.
ISBN978-3-642-01845-9
Vol.325:Shenk,ThomasE.;
Vol.338:Rothman,AlanL.(Ed.):
Stinski,MarkF.(Eds.):
DengueVirus.2009.
HumanCytomegalovirus.2008.
ISBN978-3-642-02214-2
ISBN978-3-540-77348-1
Vol.339:Spearman,Paul;Freed,EricO.(Eds.):
Vol.326:Reddy,AnireddyS.N;
HIVInteractionswithHostCellProteins.2009.
Golovkin,Maxim(Eds.):
ISBN978-3-642-02174-9
Nuclearpre-mRNAprocessinginplants.2008.
ISBN978-3-540-76775-6
Vol.340:Saito,Takashi;Batista,FacundoD.(Eds.):
ImmunologicalSynapse.2010.
Vol.327:Manchester,Marianne;Steinmetz,
ISBN978-3-642-03857-0
NicoleF.(Eds.):
VirusesandNanotechnology.2008.
Vol.341:Bruserud,Øystein(Ed.):
ISBN978-3-540-69376-5
TheChemokineSysteminClinical
andExperimentalHematology.2010.
Vol.328:vanEtten,(Ed.):
ISBN978-3-642-12638-3
LesserKnownLargedsDNAViruses.2008.
ISBN978-3-540-68617-0
Vol.342:Arvin,AnnM.(Ed.):
Varicella-zosterVirus.2010.
Vol.329:Griffin,DianeE.;
ISBN978-3-642-12727-4
Oldstone,MichaelB.A.(Eds.):Measles.2009.
ISBN978-3-540-70522-2
Vol.343:Johnson,JohnE.(Ed.):
CellEntrybyNon-EnvelopedViruses.2010.
Vol.330:Griffin,DianeE.;
ISBN978-3-642-13331-2
Oldstone,MichaelB.A.(Eds.):Measles.2009.
ISBN978-3-540-70616-8
Vol.345:Simon,M.Celeste(Ed.):
DiverseEffectsofHypoxiaonTumor
Vol.331:Villiers,E.M.de(Ed.):
Progression.2010.
TTViruses.2009.ISBN978-3-540-70917-8
ISBN978-3-642-13328-2
Vol.332:KarasevA.(Ed.):
Vol.346:ChristianRommel;BartVanhaesebroeck;
PlantproducedMicrobialVaccines.2009.
PeterK.Vogt(Ed.):
ISBN978-3-540-70857-5
Phosphoinositide3-kinaseinHealth
Vol.333:Compans,RichardW.; andDisease.2010.
Orenstein,WalterA.(Eds.): ISBN978-3-642-13662-7
VaccinesforPandemicInfluenza.2009.
Vol.347:ChristianRommel;BartVanhaesebroeck;
ISBN978-3-540-92164-6
PeterK.Vogt(Ed.):
Vol.334:McGavern,Dorian;Dustin,Micheal(Eds.): Phosphoinositide3-kinaseinHealth
VisualizingImmunity.2009. andDisease.2010.
ISBN978-3-540-93862-0 ISBN978-3-642-14815-6
Lyubomir Vassilev David Fry
l
Editors
Small-Molecule Inhibitors
of Protein-Protein
Interactions
Editors
Dr.LyubomirVassilev Dr.DavidFry
DiscoveryOncology DiscoveryTechnologies
RocheResearchCenter RocheResearchCenter
Hoffmann-LaRocheInc. Hoffmann-LaRocheInc.
340KingslandStreet 340KingslandStreet
Nutley,NewJersey07110 Nutley,NewJersey07110
USA USA
[email protected] [email protected]
ISSN0070-217X
ISBN:978-3-642-17082-9 e-ISBN:978-3-642-17083-6
DOI10.1007/978-3-642-17083-6
SpringerHeidelbergDordrechtLondonNewYork
#Springer-VerlagBerlinHeidelberg2011
Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialis
concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting,
reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationofthispublication
orpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLawofSeptember9,
1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfromSpringer.Violations
areliabletoprosecutionundertheGermanCopyrightLaw.
Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnot
imply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotec-
tivelawsandregulationsandthereforefreeforgeneraluse.
Coverdesign:Deblik,Berlin
Printedonacid-freepaper
SpringerispartofSpringerScience+BusinessMedia(www.springer.com)
Preface
Cell integrity and functions depend on a myriad of protein–protein interactions.
Manyoftheseinteractionsareinvolvedindiseaseetiologyandrepresentdesirable
targets for pharmacological intervention. However, the notion of modulating
protein–protein binding with small molecules has historically raised serious con-
cerns.Theinterfacebetweentwointeractingproteinsistypicallylargeanddevoid
ofsizablesubpockets.Ithasbeenthoughtunlikelyforadrug-likemoleculetobind
tosuch alandscape with high affinity andtoeffectively compete away oneof the
protein partners. However, this blanket characterization of protein–protein inter-
facesisoverlysimplistic.Ithasbecomeclearthatincertaincasesreasonablysized
pocketsexisttosupportbinding,orthatinothercasestheinterfaceregionisflexible
and an incoming molecule can induce the formation of a suitable binding pocket.
Ontheothersideoftheissue,theconceptofwhatconstitutesadrug-likemolecule
has been evolving, particularly in the context of protein–protein modulators. The
traditionalprofileofanorganiccompoundwithamolecularweightinthe200–500
range has been expanded to include compounds of significantly higher molecular
weight, and the possibility of using peptides and peptide-like molecules as drugs
hasbecomemuchmorerealistic.
In recent years, several success stories have appeared with regard to discovery
of protein–protein interaction inhibitors. There is a growing understanding of the
criticalfactorsinvolvedandofthefundamentalissuesrelatingtothemanyaspects
of the process – choosing targets, finding leads, discerning and verifying binding
strategies,andoptimizingproperties.Inthisvolume,wehavecollectedtheknowl-
edgeable insights of a number of leaders in this field – researchers who have
achieved success in addressing the difficult problem of inhibiting protein–protein
interactions.Theydescribetheiruniqueapproachesandshareexperiences,results,
thoughts, and opinions. The content of the chapters is rich, and in terms of scope
rangesfromgeneralizedapproachestospecificcasestudies.Therearevariousfocal
points, including methodologies and the molecules themselves. Ultimately, there
arenumerouslessonstobetakenawayfromthiscollection,andwehopethatthis
snapshot of the current state of the art in developing protein–protein inhibitors
v
vi
notonlypaystributetothepastsuccessesbutalsogeneratesexcitementaboutthe
futurepotentialofthisfield.
Nutley,NewJersey LyubomirVassilev
DavidFry
Contents
Hydrogen-BondedSyntheticMimicsofProteinSecondaryStructure
asDisruptorsofProtein–ProteinInteractions ............................... 1
MarcJ.Adler,AndrewG.Jamieson,andAndrewD.Hamilton
Small-MoleculeInhibitorsofIL-2/IL-2R:LessonsLearned
andApplied .................................................................... 25
C.G.M.WilsonandM.R.Arkin
SmallMoleculeInhibitorsoftheHumanPapillomavirus
E1–E2Interaction ............................................................. 61
PeterW.White,Anne-MarieFaucher,andNathalieGoudreau
DesignofSmall-MoleculeSmacMimeticsasIAPAntagonists ............ 89
ShaomengWang
Small-MoleculeInhibitorsRevealaNewFunctionforBcl-2
asaProangiogenicSignalingMolecule ..................................... 115
BenjaminD.ZeitlinandJacquesE.No¨r
Small-MoleculeModulatorsofc-Myc/MaxandMax/MaxInteractions ... 139
ThorstenBerg
Small-MoleculeInhibitorsofthep53–MDM2Interaction ................ 151
BinhT.VuandLyubomirVassilev
Index .......................................................................... 173
vii
.
Contributors
Marc J. Adler Chemistry Research Laboratory, University of Oxford, 12
Mansfield Road, Oxford OX1 3TA, UK
M.R.Arkin SmallMoleculeDiscoveryCenter,UniversityofCalifornia,San
Francisco, CA 94158, USA, [email protected]
Thorsten Berg Institute of Organic Chemistry, University of Leipzig,
Johannisallee 29, 04103 Leipzig, Germany, [email protected]
Anne-Marie Faucher Boehringer Ingelheim (Canada) Ltd, 2100 Cunard St.,
Laval, H7S 2G5 QC, Canada
Nathalie Goudreau Boehringer Ingelheim (Canada) Ltd, 2100 Cunard St.,
Laval, H7S 2G5 QC, Canada
AndrewD.Hamilton ChemistryResearchLaboratory,UniversityofOxford,
12MansfieldRoad,OxfordOX13TA,UK,[email protected]
AndrewG.Jamieson ChemistryResearchLaboratory,UniversityofOxford,
12 Mansfield Road, Oxford OX1 3TA, UK
Jacques E. No¨r Angiogenesis Research Laboratory, Department of
Restorative Sciences, University of Michigan School of Dentistry, Ann
Arbor, MI, USA and Department of Biomedical Engineering, University of
Michigan College of Engineering, Ann Arbor, MI, USA and Department of
Otolaryngology,UniversityofMichiganSchoolofMedicine,AnnArbor,MI,
USAandComprehensiveCancerCenter,UniversityofMichigan,AnnArbor,
MI 48109, USA, [email protected]
ix