Chemogenomics:Chemogenomics 19/4/07 16:30 Page 57 Genomics CHEMOGENOMICS a gene family approach to parallel drug discovery Currently available drugs only target around 500 different proteins4. Recent reports from efforts to sequence the human genome suggest there are tens of thousands of genes1,2 and many more different proteins. Popular estimates of the number of ‘new’ drug targets that will emerge from genomic research range from 2,000 to 5,0003. A critical question as we enter the post-genomic world is: how can the pharmaceutical industry rapidly discover and develop medicines for these new targets to improve the human condition? n the pharmaceutical industry to date, research QSAR, structure-based drug design and informat- By Dr Paul R. Caron, and early development activities have typically ics, have accelerated the drug discovery process4. Dr Michael D. Ibeen organised according to therapeutic area. Dramatically new and different drug discovery Mullican, Dr Robert In organising their drug discovery efforts in this approaches, however, are needed to take full D. Mashal, Dr Keith P. way, companies have sought to create efficiency by advantage of the massive influx of targets being Wilson, Dr Michael S. building a critical mass of expertise and experience elucidated through genomic research. Simply stat- Su and Dr Mark A. in the biology of related diseases. Over the past 20- ed, a therapeutic area focus and a single target Murcko 30 years this organisational approach has proved drug discovery approach do not create enough effi- successful for many companies. While there is no ciency to allow companies to keep pace with the doubt that this strategy produces some synergies in massive inflows of new target information. An early stage research, greater efficiency in late-stage ideal solution would be to accelerate drug discov- clinical development and marketing is the main ery by processing multiple related targets in paral- driver for the organisation of research and devel- lel, reusing information and know-how across tar- opment resources along therapeutic area lines. gets in a way that allows chemistry to be broadly Pharmaceutical companies have also traditional- leveraged. Drug discovery approaches that focus ly tackled one protein target at a time in drug dis- on structurally similar protein families, and thus covery. Over the years, increasingly sophisticated leverage the way which particular classes of chem- technologies and approaches have increased the ical compounds will interact with targets within efficiency of drug discovery based on single targets the same family, may be just such an ideal solution. at a pace sufficient to keep the pipelines of many Just as the fields of genomics and proteomics are major companies well-stocked with promising broadly characterised as the identification and development candidates. The development and classification of all the genes and proteins in a application of high-throughput chemical synthesis genome, the field of chemogenomics may be char- and in vitro biological screening, for example, as acterised as the discovery and description of all well as new computational methods applied to possible drugs to all possible drug targets5. Drug Discovery World Fall 2001 57 Chemogenomics:Chemogenomics 19/4/07 16:30 Page 58 Genomics Figure 1 Scaffold morphing and target hopping are two key concepts in chemogenomics. Scaffold morphing is the generation of multiple, chemically distinct lead classes (‘scaffolds’) against any particular target. Target hopping is the ability of compounds from the same lead classes to interact with multiple targets – in effect, to be ‘reused’. Importantly, while the scaffold class is reusable, different specific compounds from the same scaffold class will be optimal for different targets in the family Analogous to genomics and proteomics, success in tion and robotics-has helped to increase the effi- chemogenomics will require not only highly inte- ciency of drug discovery in important ways. The grated technology and computational advances, requirement of practical expertise in many parts of but will necessitate fundamental changes in the of the drug discovery process, however, suggest pharmaceutical drug discovery process. Any signif- that there is a limit to the efficiency that will be cre- icant progress towards this goal could generate a ated by automation. formidable package of patentable drug molecules. A major potential source of efficiency in any process lies in the reuse of information and know- Organising research by gene family how. A gene family approach to drug discovery Industrialising parts of the drug discovery process- seeks to exploit this efficiency to its maximum. by incorporating parallel processing, miniaturisa- Targets within a gene family – defined by homol- ogy at the protein sequence level – will often have very similar in vitro assays and properties, provid- ing some leverage of biology resources. In addi- Chemogenomics is distinct from chemical genetics. Chemical genetics tion, a significant percentage of compounds (sometimes called ‘reverse chemical genetics’) entails the use of defined designed and synthesised against one family mem- chemical probes to help understand biological targets and pathways. The ber will be active against other family members, which can allow medicinal chemistry on multiple fundamental premise is that chemical probes, if of sufficient potency and targets to have a common starting point. In addi- selectivity in cellular or animal models, can be used to help understand and tion to creating efficiency, reuse of chemical and to prioritise those targets of the greatest therapeutic relevance. Thus chemical biological information may produce intellectual genetics as currently described in the literature is essentially a ‘target property that is transferable among related tar- gets. Some of these concepts have been touched validation’ technology. Chemogenomics, on the other hand, is principally a upon by other groups7-11. ‘chemical’ technology which aims to produce new chemical entities (NCEs) – Based on our experience with employing struc- clinical development candidates – as efficiently as possible. The molecules tural biology and modelling approaches together which derive from the chemogenomics approach can of course be used as with combinatorial and medicinal chemistry, we have found that it is possible to design multiple chemical probes in a ‘target validation’ sense as well. classes of compounds to inhibit each target within a gene family. We refer to this as scaffold morphing. 58 Drug Discovery World Fall 2001 Chemogenomics:Chemogenomics 19/4/07 16:30 Page 60 Genomics Figure 2 Sequence homology is often a good predictor of three- dimensional structural homology. On the left panel is the crystal structure of caspase-1 (ICE) colour coded by the sequence homology of a set of 10 different caspases. Blue = highly conserved sequences, white = intermediate homology, and red = low homology. On the left panel is the crystal structure of caspase-1 colour coded by the three- dimensional structural variation in the C-α, positions taken from a superposition of five different caspases. Blue = highly conserved C-α positions, white = intermediate and red = low structural conservation Once created, the molecular libraries may be The completed genome sequence enables the screened against multiple targets within the family, identification and classification of all members of a and the breadth of activity of each active chemical gene family into subfamilies based on a number of scaffold may be rapidly explored. This ‘compound criteria: overall sequence homology, domain struc- reuse’ strategy is sometimes called target hopping. ture, and/or transcriptional regulation. This The combination of ‘morphing and hopping’ are genome-wide perspective distinguishes chemoge- essential for the rapid generation of multiple devel- nomics from traditional gene family research. opment candidates against multiple targets within a family (Figure 1). The need for therapeutic area The three-dimensional structures of approxi- knowledge mately 15,000 proteins are now publicly available A central tenet of the chemogenomic approach is and there is a recent surge of interest in the public that efficiencies will result from reuse of informa- and private sector to actively obtain representative tion and compounds, driven by the overlap structures for novel proteins. The combination of between chemical space and the active sites of the this raw data and refined homology modelling protein family members. Maximal increases in effi- tools is now enabling the structures of a large num- ciency and productivity can only occur when this ber of pharmaceutically relevant protein targets to knowledge is concentrated in a single discovery be predicted as well as the shapes and physical unit which is organised along areas of ‘chemoge- properties of potential ligand binding sites. The nomic space’. We believe it is possible to have this ability to map genomic data on to protein struc- organisational structure from project initiation tures provides the framework linking three billion through first in man studies. As, Cs, Gs and Ts to drug design chemistry. A distinct advantage of this discovery structure 60 Drug Discovery World Fall 2001 Chemogenomics:Chemogenomics 19/4/07 16:30 Page 61 Genomics entire target family, together with a representative References subset of protein structures, allows one to build 1 Lander ES, Linton LM, Birren three-dimensional models for