Introduction to Biological and Small Molecule Drug Research and Development: theory and case studies

445 Pages·20.518 MB·English

by  Ganellin C.R., Jefferis R., Roberts S.M. (Eds.)

Introduction to Biological
and Small Molecule Drug
Research and Development
Theory and Case Studies
Edited By
Robin Ganellin
Stanley Roberts
Roy Jefferis
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Biographies
Stanley M. Roberts was appointed honorary visiting professor in the School of Chemistry at the
University of Manchester in 2004. Previously he held posts in other universities in the UK (Salford
1972–80;Exeter1986–95;Liverpool1995–2004)andinindustry(HeadofChemicalResearch,Glaxo,
Greenford,UK),beforemovingtoManchesterUniversitytobecomefounderandinauguraldirectorof
the Biotech. CentreCoEBio3.
Dr A. J.Gibb is currently reader in pharmacology at UniversityCollege London, UK. He grad-
uated in biochemistry and pharmacology and completed his PhD at the University of Strathclyde.
Hewasappointedlecturerin pharmacologyatUCLin1990 andteachespharmacology tostudents
in medicine, biomedical sciences, natural sciences, medicinal chemistry and pharmacology. He is
apasteditoroftheJournalofPhysiologyandoftheBritishJournalofPharmacology.Hecurrently
leads the General and Advanced Receptor Theory Workshop for the British Pharmacological
Society Diploma in Pharmacology. He has published over 50 research papers, reviews and con-
tributions to books. His current main research interest is in the pharmacology and function of
NMDA receptors.
Prof.JenniferLittlechildisprofessorofbiologicalchemistryanddirectoroftheHenryWellcome
Centre for Biocatalysis at Exeter. She carried out her PhD in the Biophysics Laboratory, Kings
College,LondonUniversity,UKfollowedbyapostdoctoralfellowshipatthebiochemistrydepartment
at Princeton university, USA. In 1975, she became a group leader at the Max Planck Institute for
MolecularGeneticsinBerlin,Germany.In1980,shereturnedtotheUKtoBristolUniversityandin
1991toExeter.HercurrentresearchgrantsarefromUKresearchcouncils,BBSRC,EPSRCandthe
EU andlargeand SME industries.
Her research studies involve the structural and mechanistic characterisation of the C–C bond
forming enzymes transketolase and aldolase, vanadium haloperoxidases, Baeyer–Villiger mono-
oxygenases,aminoacylases,novelesterasesandlipases,gammalactamases,alcoholdehydrogenases,
dehalogenases, transaminases and other enzymes from thermophilic bacteria and archaea. Many of
theseenzymesareusedincombinationwithconventionalchemicalsynthesisfortheproductionofnew
opticallypuredrugsofinteresttopharmaceuticalcompanies.Shehaspublishedover120publications
in refereed high impact journalsand presented her researchworkinternationally.
Dr Michael Stocks is currently associate professor in medicinal chemistry in the school of
pharmacyattheUniversityofNottingham.HereceivedhisPhDfromSouthamptonUniversity(1991)
under the supervision of Prof. Philip Kocienski and has worked for Fison’s Pharmaceuticals, Astra
Pharmaceuticals and AstraZeneca. He has wide experience and successful delivery of projects in
GPCR,enzymeandionchanneldrugdiscoveryinboththeleadoptimisationandgenerationphases.
JillM.Carton,director,BiologicsResearch,BiotechnologyCenterofExcellence,JanssenR&D.
Dr Jill Carton received her PhD in molecular and cellular biology from Fordham University,
NewYork.WhileatFordham,Jillidentifiedandcharacterizednovelinterferon-regulatedgenesandthe
rolethegeneproductsplayininterferon’santiviralandantiproliferativeactivities.Followinggraduate
xiii
xiv Biographies
school,JilltookapostdoctoralfellowshipatJohnson&Johnson,PharmaceuticalResearchInstitute.In
2000,JilltransferredintoaresearchscientistpositionatCentocor,Inc.workingonthediscoveryand
developmentofmonoclonalantibodytherapeutics.Since2000,JillhasworkedinBiologicsResearch
with particular interest in early discovery projects through therapeutic project transition from
discovery to development. Currently, Jill heads the Molecular and Protein Biosciences group at
Janssen R&D supportingthe biologics discovery portfolio.
William R. Strohl, vice president, Biologics Research, Biotechnology Center of Excellence,
JanssenR&D.DrWilliamStrohlreceivedhisPhDinmicrobiologyfromLouisianaStateUniversity,
and worked as a researcher at GBF, Braunschweig, Germany. From 1980 to 1997, he rose from
assistant to full professor in the Department of Microbiology and Program of Biochemistry at The
OhioStateUniversity,researchingnaturalproductbiosynthesis.In1997,DrStrohlmovedtoMerckto
lead Natural Products Microbiology, and then from 2001 to 2008, Dr Strohl was a leader in Merck
monoclonal antibody discovery. In April 2008, Dr Strohl joined Centocor to lead antibody drug
discovery,andthenwaspromotedtovicepresident,BiologicsResearch,BiotechnologyCOE,Janssen
R&D. Dr Strohl has over 120 publications and has recently written the book “Therapeutic Antibody
Engineering: Current and Future Advances Driving the Strongest Growth Area in the Pharma
Industry” (WoodheadPublishing, October2012).
JamesSamanen isapharmaceuticalconsultantwithatrackrecord of30+yearsleadership and
innovation in drug discovery project and portfolio management, and portfolio data analysis at
GlaxoSmithKline. While at GSK, James helped in developing and implementing worldwide Port-
folioManagementforGlaxoSmithKlineDiscoveryandGeneticsResearchbusinessesencompassing
2000staffand$400Mbudgetdinvolvingnegotiationandimplementationofprocessesforselection
and prioritization of research programmes, developing IT systems, mirroring past to present
performance with fit-for-purpose benchmarking analysis, modeling future performance, change
management and team training. His work enabled an increase in productivity of drug-like leads in
GSK by >50% in 2 years by cross-functional team working, prioritization and 40% portfolio
downsizing. He also enabled strategy changes reducing cycle times by 50%. As a group leader in
medicinalchemistryhediscoveredandchampionedlotrafiban(antithrombotic)toPhaseIII,andtwo
preclinicalcandidateantithrombotics.Hehasbeenaprojectleaderindiverseareasofdrugdiscovery
and authored 25 patent applications and over 95 publications. He established James Samanen
Consulting in December 2008.
MatthewP.CoghlaniscurrentlyaprojectdirectorleadingCardiovascularandMetabolicDisease
ResearchandEarlyDevelopmentProjectsatMedImmune(Cambridge,UK);thebiologicsdivisionof
AstraZeneca.PreviouslyDrCoghlanwastaskedwithoverseeingthegrowthofthebiologicsportfolio
in the cardiovascular and gastrointestinal therapy area at MedImmune/AstraZeneca (2008–2010).
Prior to entering biologics R&D in early 2008, Dr Coghlan led in vitro biology teams and small
molecule research projects in the metabolic disease therapy area at SmithKline Beecham and
AstraZeneca (1998–2007). Dr Coghlan has published over 25 scientific papers and reviews.
Dr Coghlan has a 1st class honours degree in biochemistry from Imperial College, University of
London,andaPhDfromtheUniversityofCambridge.DrCoghlanconductedpostdoctoralresearchat
Harvard Medical School asa recipient ofNATORoyal Society Fellowship.
Biographies xv
David Fairman is a pharmacodynamic/pharmacokinetic modeller working within the clinical
pharmacology and drug metabolism and pharmacokinetics (DMPK) department at MedImmune
(Cambridge,UK),thebiologicsdivisionofAstraZeneca.Hiscurrentportfolioofpreclinicalandclinical
biologicsprojectsspansacrosstheoncologyandcardiovascularandgastrointestinaltherapyareaswith
afocusondiabetes.Immediatelypriortothispositionheledthepreclinicalmodellingteamwithinthe
allergy and respiratory areas within Pfizer (Sandwich, UK) and was responsible for the delivery of
multiplesmallmoleculecandidatesforevaluationinhumanclinicalstudies.Earlierinhiscareerheled
DMPK and wider research teams within the allergy and respiratory and cardiovascular areas. David
FairmanhasaBScinpharmacologyfromtheopenuniversity,anMScinmodellingandsimulationfrom
theUniversityofManchesterandhasauthoredorco-authoredover10scientificpapers.
Dr Andy Barker is currently an independent scientific consultant. He trained as an organic
chemist at Nottingham University with Prof. Gerry Pattenden and has held positions at Beecham
Pharmaceuticals,HoechstandAstraZenecaworkingindrugdiscoverygroupsasamedicinalchemist,
projectleaderandmanagerofthechemistrydepartment.Hehasexperienceinavarietyoftherapeutic
areasandhasbeenthememberorleaderofprojectteams,whichhaveput12drugsintodevelopment,
two of which have reached the market. He was awarded the American Chemical Society ‘Hero of
Chemistry’ awardin2011.
DrDavidAndrewstrainedasapharmacistatNottinghamUniversityandthenasaPhDorganic
chemistunderthesupervisionofDrsIanGalpinandRickCosstickatLiverpoolUniversity.From1990
to2003,heheldpositionsatGlaxoSmithKlineasamedicinalchemist,projectleaderanddepartment
director. Since 2003, he has worked as an associate director in the oncology iMed chemistry
department of AstraZeneca. He has experience of working in CNS, inflammation, antiviral and
oncology discovery and development chemistry. He currently heads AstraZeneca’s oncology lead
generationchemistry group.
Dr M. Hasmann is a preclinical science leader and project team leader at Roche’s Pharma
ResearchandEarlyDevelopment(pRED)unitinPenzberg,Germany(since2002).Previously,hewas
HeadofCellCultureLaboratoriesatKlingePharmaGmbH(Fujisawagroup;1987–2001).Hismain
backgroundismicrobiology(Technical UniversityMunich, Germany)andcellbiology(MaxPlanck
InstituteforBiochemistry,Martinsried,Germany).Hehasessentiallycontributedtoseveralearlyand
latestageoncologyresearchanddevelopmentprogrammesincludingsmallmoleculesandtherapeutic
antibodies.
Prof. W. Jelkmann is currently Chairman of the Institute of Physiology at the University of
Luebeck,Germany.AfterstudyingmedicineinHannover(1967–73),heworkedatuniversityinstitutes
inRegensburg,NewOrleansandBonn.Hisresearchinterestsincludehemopoieticgrowthfactorsand
cytokineswithemphasisonerythropoietin,thrombopoietinandvascularendothelialgrowthfactor.He
has authored over 150 original publications, 130 review articles/book chapters and (co-)edited five
books.
Charles W. Richard III is currently the Chief Medical Officer of Oxyrane, a biotechnology
company devoted to discovering and developing next-generation enzyme replacement products for
xvi Biographies
lysosomal storage disorders. Previously he held positions as Head of translational medicine at Shire
Human Genetic Therapies (2006–2012); vice president and Head of the genomics department at
Wyeth Research (1997–2005), and assistant professor of psychiatry and human genetics at the
UniversityofPittsburgh(1992–1995).DrRichardholdsanMDandPhDfromOhioStateUniversity
andaBSinbiologyfromStanfordUniversity,andhaspublishedover40scientificpapersandreviews.
Arun K. Ghosh is currently the Ian P. Rothwell Distinguished Professor of Chemistry and
MedicinalchemistryatPurdueUniversity.HereceivedhisBSinChemistryandMSinChemistryfrom
the University of Calcutta and Indian Institute of Technology, Kanpur, respectively. He obtained his
PhDinorganicchemistry(1985) fromUniversityofPittsburghandpursuedpostdoctoralresearchat
Harvard university (1985–1988). He was a research fellow at Merck Research Laboratories and in
1994,hejoinedUniversityofIllinois,Chicagoasanassistantprofessor,eventuallybecomingprofessor
ofchemistryin1998.In2005,hemovedtoPurdueUniversity,withajointappointmentinchemistry
and medicinal chemistry. His research interests include diverse areas of organic, bioorganic, and
medicinal chemistry with particular emphasis on organic synthesis and protein–structure-based drug
design. He has published over 250 scientific papers and edited a book on aspartic acid protease as
atherapeutic target.
BrunoD.ChapsalgraduatedwithaM.Sc.inchemistry&chemicalengineeringfromtheLyon’s
school of chemistry (CPE Lyon), France. He then obtained his Ph.D. from Stony-Brook University,
NY,whereheworkedonsyntheticmethodologiesandcatalysisundertheguidanceofProfessorIwao
Ojima. In 2006, he joined the group of Professor Arun K. Ghosh at Purdue University. His post-
doctoralresearchfocusedonthestructure-baseddesignofnovelHIVproteaseinhibitorswithbroad-
spectrum activities against drug-resistant viruses. He is currently a Senior Research Scientist at
AMRI’sin-sourcing operationsat Eli Lillyand Company,Indianapolis.
Denis Mulleman, MD, PhD, is professor of rheumatology at the University of Tours (France).
HeismemberoftheCNRSresearchunit7292(team‘Antibodies,Fcreceptorsandclinicalresponses’).
His main research interest is to characterize the concentration–response relationship of anti-TNF
monoclonal antibodies and Fc-containing fusion proteins, in order to help clinicians in personalizing
drugadministration.
Marc Ohresser is a research associate in Herve´ Watier’s group at the Universite´ Franc¸ois-
Rabelais,Tours.HisinterestsfocusontherapeuticantibodiesandtheirinteractionswithFcreceptors.
He is also a member of the CNRS unit 7292 and has management responsibilities within the
Laboratory of Excellence (LabEx) ‘MAbImprove’ programme, in particular as scientific leader of
the MAbMapping exercise that maintains ‘technology watch’ and ‘patent mapping’ in the field of
therapeutic antibodies.
Herve´Watier,MD,PhD,iscurrentlyProfessorofImmunologyattheFacultyofMedicine,Tours,
France,andHeadoftheLaboratoryofImmunologyattheUniversityHospitalofTours.Hediscovered,
in2001,thatpatientshomozygousforapolymorphisminageneencodinganIgGFcreceptorbetter
responded to different therapeutic antibodies, which is now considered as a milestone in the recent
historyoftherapeuticantibodiesdevelopment.Since2009,heisDirectorofaFrenchCNRSResearch
Biographies xvii
NetworkbringingtogetherahundredofpublicorprivateFrenchresearchteams,engagedinantibody
research.Since2011,hecoordinatesthelaboratoryofexcellence(LabEx)‘MAbImprove’,aconsor-
tiumof14researchteamsfromToursandMontpellier,whose10year-programmeistheoptimization
of therapeuticantibodiesdevelopment.
Robin Ganellin led the chemistry for the discovery of histamine H2 receptors at SmithKline &
FrenchLabs(UK),isacoinventorofcimetidine(Tagamet(cid:1))andbecameVicePresidentforResearch.
He has authored over 260 scientific publications, coedited eight books and has receivedmany inter-
nationalawardsforhisworkinMedicinalChemistry.In1986,hewaselectedaFellowoftheRoyal
Society and became Professor of Medicinal Chemistry at University College London. He has been
inductedintotheUSANationalInventorsHallofFameandtheACSDivisionofMedicinalChemistry
Hall of Fame.
Preface
The history of medicines has been documented in detail but even at a broad and superficial level,
different eras emerge quite clearly. First of all, for almost 2000 years, European medicine was
dominatedbyGalen’stheoryofthehumours.Thisheldthathealthdependedonthecorrectbalanceof
thefour‘humours’,or‘principalfluids’namelyblackbile,yellowbile,phlegmandbloodproducedin
the body. The correct balance could be maintained, it was thought, by diet, blood-letting and medi-
cines.Themedicineswerenaturalproductsusedasinfusionsandmixturesbasedprimarilyonfolklore;
the early applications of morphine and quinine quickly come to mind. Indeed, some traditional
therapies are still very popular and the practice has become part of the field of ‘complementary
medicine’.
However, as it became possible to define detailed mechanisms of infection and the causes of
disease,itwasthenfeasibletodesignbiologicalassayswhichcouldleadscientiststonewtherapies.
Still,naturalproductsprovidedagoodproportionofthenewmedicines(forexample,penicillinsand
steroids) although, increasingly, these natural materials were modified to provide optimized drug
substances. In the latter half of the twentieth century, the naturally occurring small-molecule neuro-
transmitterswerebeingmodifiedtoprovideblockbusterdrugsinareassuchasheartdisease,asthma
and the treatmentof stomach ulcers.
Medicinal chemistry came to the forefront at this time; chemists manufactured molecules on
a small scale to test in the increasingly rapid (fast-throughput) assays. Novel, small molecules were
preferred to allow patent protection and easy production at the multi-kilogram/tonne scale, respec-
tively.Thoseentitiespassingthestringentsafetyrequirementsemergedasthedrugsfortheclinic.Still,
today,small-moleculechemotherapeuticsaresoughtaftertoprovidegreaterprotectionagainstcancer
and heart disease interalia aswell as debilitatingconditions such as arthritis anddementia.
The contemporaneous development of protein chemistry allowed for the identification, isolation,
purificationanduseoflargebiomoleculesasdrugs,forexample,porcineinsulin.Withtheadventof
genetic engineering, the commercial production of biomolecules ex vivo became possible, for
example, the production of human insulin in the bacterium Escherichia coli and erythropoietin in
mammaliancells.Afurtherseminaladvancewastheintroductionofhybridomatechnologythatallows
for thegenerationofhuman monoclonal antibodies ofpredefined specificity onan industrialscale.
This overall ability more efficiently to prepare selected proteins has given rise, particularly
between1991and2010,toacomplementarysetofmedicines,commonlyknownasbiopharmaceutics
orbiopharmaceuticals.Currentlyonlyca15%ofmedicinescomeintothisbracket,butthewaythings
are progressing, specifically the number of biopharmaceuticals presently in clinical trials and the
proportion ofbiopharmaceuticalsin the market place, thispercentage could doubleby 2025.
It has been a fascinating challenge for us to present the background to these two types of manu-
facturedmedicineforareaderwhoisbecominginterestedinmedicinalscience.Westartwithareview
of biological targets and the strategies to search for small molecules that might be therapies for
aparticulardisease.Havingestablishedthatbase,thestructuresandpropertiesofbiopharmaceuticals
are described before the two approaches are comparedfrom scientific and commercial perspectives.
Thecasestudiesthatareprovidedinthelaterchaptersservetoillustratethegeneralconceptswith
specificexamples.Wherepossible,largeandsmallmoleculestargetingrelatedtherapiesaregrouped
xix
xx Preface
together. Overall, the coverage encompasses major therapeutic sectors as well as niche and orphan
diseases. The clinical experiencewith the newdrugs is outlined insomedetail inmostcases.
The Editors are extremely fortunate that the many world-leading experts agreed to contribute to
this work. We are most grateful for their expositions, particularly in the chapters which describe
complex issues, wherein great effort has been made to employ comprehensible language, keeping
jargontoaminimum.
Wehopethatthebookwillprovideagoodbasistoallowthereadertostarttocompareandcontrast
the science of small-molecule chemotherapies with that ofthe peptide/proteinbiopharmaceuticals.
C. Robin Ganellin
Roy Jefferis
Stanley M. Roberts