REVIEWbph_1127 1239..1249Principles of early drugdiscoveryJP Hughes1, S Rees2, SB Kalindjian3and KL Philpott31MedImmune Inc, Granta Park, Cambridge, UK,2GlaxoSmithKline, Gunnels Wood Road,Stevenage, Hertfordshire, UK, and3King’s College, Guy’s Campus, London, UKCorrespondenceDr Karen Philpott, HodgkinBuilding, King’s College, Guy’sCampus, London SE1 1UL, UK.E-mail: karen.philpott@kcl.ac.uk----------------------------------------------------------------Keywordsdrug discovery; high throughputscreening; target identification;target validation; hit series; assaydevelopment; screening cascade;lead optimization----------------------------------------------------------------Received2 August 2010Revised7 October 2010Accepted8 November 2010Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12–15years and cost in excess of $1 billion. The idea for a target can come from a variety of sources including academic and clinicalresearch and from the commercial sector. It may take many years to build up a body of supporting evidence before selectinga target for a costly drug discovery programme. Once a target has been chosen, the pharmaceutical industry and morerecently some academic centres have streamlined a number of early processes to identify molecules which possess suitablecharacteristics to make acceptable drugs. This review will look at key preclinical stages of the drug discovery process, frominitial target identification and validation, through assay development, high throughput screening, hit identification, leadoptimization and finally the selection of a candidate molecule for clinical development.AbbreviationsADME, absorption, distribution, metabolism and excretion; DMPK, drug metabolism pharmacokinetics; DMSO,dimethyl sulphoxide; GPCRs, G-protein-coupled receptors; HTS, high throughput screening; mAbs, human monoclonalantibodies; PD, pharmacodynamic; PK, pharmacokinetic; SAR, structure–activity relationshipIntroductionA drug discovery programme initiates because there is adisease or clinical condition without suitable medical prod-ucts available and it is this unmet clinical need which is theunderlying driving motivation for the project. The initialresearch, often occurring in academia, generates data todevelop a hypothesis that the inhibition or activation ofa protein or pathway will result in a therapeutic effect in adisease state. The outcome of this activity is the selection of atarget which may require further validation prior to progres-sion into the lead discovery phase in order to justify a drugdiscovery effort (Figure 1). During lead discovery, an inten-sive search ensues to find a drug-like small molecule orbiological therapeutic, typically termed a development can-didate, that will progress into preclinical, and if successful,into clinical development (Figure 2) and ultimately be a mar-keted medicine.Target identificationDrugs fail in the clinic for two main reasons; the first is thatthey do not work and the second is that they are not safe. Assuch, one of the most important steps in developing a newdrug is target identification and validation. A target is a broadterm which can be applied to a range of biological entitieswhich may include for example proteins, genes and RNA. Agood target needs to be efficacious, safe, meet clinical andcommercial needs and, above all, be ‘druggable’. A ‘drug-gable’ target is accessible to the putative drug molecule, bethat a small molecule or larger biologicals and upon binding,elicit a biological response which may be measured both invitro and in vivo. It is now known that certain target classesare more amenable to small molecule drug discovery, forexample, G-protein-coupled receptors (GPCRs), whereas anti-bodies are good at blocking protein/protein interactions.Good target identification and validation enables increasedBJPBritish Journal ofPharmacologyDOI:10.1111/j.1476-5381.2010.01127.xwww.brjpharmacol.orgBritish Journal of Pharmacology (2011) 162 1239–1249 1239© 2011 The AuthorsBritish Journal of Pharmacology © 2011 The British Pharmacological Societyconfidence in the relationship between target and disease andallows us to explore whether target modulation will lead tomechanism-based side effects.Data mining of available biomedical data has led to asignificant increase in target identification. In this context,data mining refers to the use of a bioinformatics approach tonot only help in identifying but also selecting and prioritiz-ing potential disease targets (Yang et al., 2009). The datawhich are available come from a variety of sources butinclude publications and patent information, gene expres-sion data, proteomics data, transgenic phenotyping and com-pound profiling data. Identification approaches also includeexamining mRNA/protein levels to determine whether theyare expressed in disease and if they are correlated with diseaseexacerbation or progression. Another powerful approach is tolook for genetic associations, for example, is there a linkbetween a genetic polymorphism and the risk of disease ordisease progression or is the polymorphism functional. Forexample, familial Alzheimer’s Disease (AD) patients com-monly have mutations in the amyloid precursor protein orpresenilin genes which lead to the production and depositionin the brain of increased amounts of the Abeta peptide, char-acteristic of AD (Bertram and Tanzi, 2008). There are alsoexamples of phenotypes in humans where mutations cannullify or overactivate the receptor, for example, the voltage-gated sodium channel NaV1.7, both mutations incur a painphenotype, insensitivity or oversensitivity respectively (Yanget al., 2004; Cox et al., 2006).An alternative approach is to use phenotypic screening toidentify disease relevant targets. In an elegant experiment,Kurosawa et al. (2008) used a phage-display antibody libraryto isolate human monoclonal antibodies (mAbs) that bind tothe surface of tumour cells. Clones were individually screenedby immunostaining and those that preferentially and stronglystained the malignant cells were chosen. The antigens recog-nized by those clones were isolated by immunoprecipitationand identified by mass spectroscopy. Of 2114 mAbs withunique sequences they identified 21 distinct antigens highlyexpressed on several carcinomas, some of which may be usefultargets for the corresponding carcinoma therapy and severalmAbs which may become therapeutic agents.Target
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