BJP British Journal of Pharmacology REVIEW bph 1127 DOI 10 1111 j 1476 5381 2010 01127 x www brjpharmacol org Correspondence 1239 1249 Dr Karen Philpott Hodgkin Building King s College Guy s Campus London SE1 1UL UK E mail karen philpott kcl ac uk Principles of early drug discovery Keywords JP Hughes1 S Rees2 SB Kalindjian3 and KL Philpott3 1 MedImmune Inc Granta Park Cambridge UK 2GlaxoSmithKline Gunnels Wood Road Stevenage Hertfordshire UK and 3King s College Guy s Campus London UK drug discovery high throughput screening target identification target validation hit series assay development screening cascade lead optimization Received 2 August 2010 Revised 7 October 2010 Accepted 8 November 2010 Developing a new drug from original idea to the launch of a finished product is a complex process which can take 12 15 years and cost in excess of 1 billion The idea for a target can come from a variety of sources including academic and clinical research and from the commercial sector It may take many years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme Once a target has been chosen the pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs This review will look at key preclinical stages of the drug discovery process from initial target identification and validation through assay development high throughput screening hit identification lead optimization and finally the selection of a candidate molecule for clinical development Abbreviations ADME absorption distribution metabolism and excretion DMPK drug metabolism pharmacokinetics DMSO dimethyl sulphoxide GPCRs G protein coupled receptors HTS high throughput screening mAbs human monoclonal antibodies PD pharmacodynamic PK pharmacokinetic SAR structure activity relationship Introduction Target identification A drug discovery programme initiates because there is a disease or clinical condition without suitable medical products available and it is this unmet clinical need which is the underlying driving motivation for the project The initial research often occurring in academia generates data to develop a hypothesis that the inhibition or activation of a protein or pathway will result in a therapeutic effect in a disease state The outcome of this activity is the selection of a target which may require further validation prior to progression into the lead discovery phase in order to justify a drug discovery effort Figure 1 During lead discovery an intensive search ensues to find a drug like small molecule or biological therapeutic typically termed a development candidate that will progress into preclinical and if successful into clinical development Figure 2 and ultimately be a marketed medicine Drugs fail in the clinic for two main reasons the first is that they do not work and the second is that they are not safe As such one of the most important steps in developing a new drug is target identification and validation A target is a broad term which can be applied to a range of biological entities which may include for example proteins genes and RNA A good target needs to be efficacious safe meet clinical and commercial needs and above all be druggable A druggable target is accessible to the putative drug molecule be that a small molecule or larger biologicals and upon binding elicit a biological response which may be measured both in vitro and in vivo It is now known that certain target classes are more amenable to small molecule drug discovery for example G protein coupled receptors GPCRs whereas antibodies are good at blocking protein protein interactions Good target identification and validation enables increased 2011 The Authors British Journal of Pharmacology 2011 The British Pharmacological Society British Journal of Pharmacology 2011 162 1239 1249 1239 BJP JP Hughes et al Figure 1 Drug discovery process from target ID and validation through to filing of a compound and the approximate timescale for these processes FDA Food and Drug Administration IND Investigational New Drug NDA New Drug Application Target validation Compound screening secondary assays In vivo analysis inhibition Candidate Enzyme Receptor Genetic cellular and in vivo experimental models to identify and validate target HTS selective library screens structure based design Reiterative directed compound synthesis to improve compound properties in vitro ex vivo secondary assays mechanistic Selectivity liability assays Compound pharmacology Disease efficacy models Early safety toxicity studies Preclinical safety toxicity package Figure 2 Overview of drug discovery screening assays confidence in the relationship between target and disease and allows us to explore whether target modulation will lead to mechanism based side effects Data mining of available biomedical data has led to a significant increase in target identification In this context data mining refers to the use of a bioinformatics approach to not only help in identifying but also selecting and prioritizing potential disease targets Yang et al 2009 The data which are available come from a variety of sources but include publications and patent information gene expression data proteomics data transgenic phenotyping and compound profiling data Identification approaches also include examining mRNA protein levels to determine whether they are expressed in disease and if they are correlated with disease exacerbation or progression Another powerful approach is to look for genetic associations for example is there a link between a genetic polymorphism and the risk of disease or disease progression or is the polymorphism functional For example familial Alzheimer s Disease AD patients commonly have mutations in the amyloid precursor protein or presenilin genes which lead to the production and deposition in the brain of increased amounts of the Abeta peptide characteristic of AD Bertram and Tanzi 2008 There are also examples of phenotypes in humans where mutations can 1240 British Journal of Pharmacology 2011 162 1239 1249 nullify or overactivate the receptor for example the voltagegated sodium channel NaV1 7 both mutations incur a pain phenotype insensitivity or oversensitivity respectively Yang et al 2004 Cox et al 2006 An alternative approach is to use phenotypic screening to identify disease relevant targets In an elegant
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