US-driven trends in combinatorial chemistry

Chris Tils

Issue: Combinatorial Chemistry is set to become a core technology for pharmaceutical and chemical companies. In combination with technologies such as High Throughput Screening (HTS), robotics, advanced software and genetics, it has the ability to shorten the time to market for new drugs and make drug discovery a less costly process. Combinatorial chemistry is now also moving into new fields of application like agrochemicals and advanced materials.

Relevance: European chemical and pharmaceutical companies have acquired the technology through joint ventures, consortia or take-overs of small firms, which are mostly located in the USA, and almost none in Europe. This is possibly due to the fact that Combinatorial Chemistry partly has its origin in dedicated biotechnology firms, which are much more abundant in the USA than in Europe. This underlines once again the importance of small high-tech firms as source of new technological developments and points to the need for an examination of policy implications.

Analysis

The last few years we have observed a peak in the attention given to combinatorial chemistry. Articles in scientific journals suggest that these developments will lead to a revolution in drug discovery processes and in several other areas of application. From a European perspective it may be interesting to note that the technology seems to be almost exclusively developed in the USA.

In this article, we explain what combinatorial chemistry is and what future technological trends and spin-offs can be expected. We will also discuss the relationship between biotechnology and combinatorial chemistry and will argue that it is most probable that the USA is leading in combinatorial chemistry, because it is stronger in biotechnology than Europe is. To continue, we discuss Europe's response to these developments. The article ends by signalling certain policy implications.

What is combinatorial chemistry?

Pharmaceutical companies face considerable pressure to develop new drugs in a less costly and time consuming way. Powerful health care organizations demand cheaper drugs. At the same time scientific research, for example through the Human Genome Project, is revealing more and more possible targets for tackling diseases. Moreover, a number of resistant pathogens and new diseases like AIDS require new drugs quickly. Combinatorial chemistry provides a tool to meet these demands for cuts in costs and time. Traditionally, chemists in the pharmaceuticals business had to synthesize possible drug candidates one by one before they could screen the activity of the candidate. The basic idea of combinatorial chemistry is to synthesize rapidly large amounts of different compounds at the same time, using a process that is supported by computation and automation. Combinatorial techniques enable chemists to combine several chemical building blocks in many different ways, resulting in large numbers of different compounds. The collection of compounds is called a combinatorial library. Box 1 explains in more detail how combinatorial chemistry works. The philosophy of the approach is clear: the more compounds we can screen for activity as a drug, the more chances we have for quickly finding a possible drug candidate, or in jargon: a lead. Experts expect that a lot can be saved in terms of money and time. Identifying a lead in a traditional drug discovery process typically takes approx. 3-4 years. It is expected that this step will only take 2 years using combinatorial libraries. The costs incurred in generating compounds are expected to drop by a factor of 10.

Advanced software plays a key role in combinatorial chemistry. In the first place, software is used to steer the automated synthesis and analysis of compounds. Secondly, but more importantly, there is a clear trend towards smaller and smarter libraries. It is easy to imagine that the larger a random library is, the lower the chances are of an individual compound representing a suitable drug candidate. Ways to focus a library to a specific target (disease), could lead to a higher probability of finding a suitable drug. Advanced software is developed for this purpose. Computational chemistry can 'draw a picture' of the chemical structure a drug has to tackle. Moreover, it can then 'advice' which chemical building blocks are most likely to be able to establish a 'hit' towards that structure. In jargon: software can advice on structure-activity relationships. In this way, the use of libraries gets 'smarter' and more focused.

All in all, combinatorial chemistry seems to be a promising technique. However, we should emphasize that the technology also has its limits, the most important one being that the chemical building blocks used still determine what novel leads can be discovered. It is likely that, for example, natural products will remain an important source of novel chemical building blocks for subsequent use in combinatorial chemistry technology.

The state-of-the-art and future applications

At present most pharmaceutical companies have capabilities in combinatorial chemistry. The total number of companies that list combinatorial chemistry as part of their technology base now stands at around 200. If we take an overview of the combinatorial scene we can see that a new industry has emerged comprising firms based exclusively on combinatorial chemistry. The amounts of money invested in this industry are considerable: in the USA the capital raised by combinatorial chemistry companies was around 600 million dollars in 1996 (By way of comparison between July 94- June 95, US biotechnology firms were capable of raising roughly 3.5 times as this amount). Considering the fact that combinatorial chemistry is a very recent development, the amount of capital invested in it is remarkable. Whether the investments pay off will depend on the amount of new products and applications combinatorial chemistry creates and when they appear. At this stage it is not possible to predict what the importance of the technology will be from a financial point of view. However, the expectations are high, certainly considering the degree to which the technology already shows promising results.

Pharmaceutical companies already have the first drugs designed by combinatorial chemistry in the clinical trials phase. These are products intended to combat the pain of cancer, migraine and arteriosclerosis. The trials suggest that the promise of shortening the time to market seems likely to be fulfilled. Market approval of drugs developed by combinatorial chemistry seems to be a question of time. Though combinatorial chemistry has so far mostly been applied in the pharmaceuticals sector, other industrial sectors are also affected by the technology. Recently, the agro-chemicals sector started to use combinatorial chemistry techniques to look for new leads, for example for insecticides and fungicides. It makes sense for this sector to follow the pharmaceuticals sector in taking up combinatorial chemistry. In both sectors it is important to be able to rapidly screen large amounts of compounds for biological activity.

The interesting point is that applications of combinatorial chemistry techniques are diffusing into others arenas than just those where some kind of biological activity or effect is sought. The technology is now also being applied in the search for new materials. Recently, US investigators were able to use combinatorial chemistry successfully in their search for high-temperature super-conducting materials. The investigators composed a library of materials based on elements that were screened for their superconductivity. The technology has also been used to trace thin-film batteries, new liquid crystals for flat screens or new catalysts. The crucial feature of combinatorial chemistry today appears to be the ability to combine an almost endless range of substances and to screen them for whatever feature, instead of just biological activity.

In conclusion, combinatorial chemistry currently plays and will continue to play, a role in pharmaceuticals, agro-chemicals and new materials. However, we should point out that these are not the only fruits of combinatorial chemistry. Specialized robotics and software should also be considered as important spin-off applications of the technology.

USA biotechnology and combinatorial chemistry

In the USA there is a close connection between the industrial structure of biotechnology and combinatorial chemistry. In recent years it is even common for a good deal of biotechnology firms not only to hire bio(techno)logists, but also combinatorial chemists. There are good reasons for this: also from a technological point of view, there are connections, which we describe below.

Firstly, biotechnology serves combinatorial chemistry as a provider of new targets. Over the last two decades, pharmaceutical and biotechnology companies have been working towards a clarification of the biological mechanisms which underlie disease. The Human Genome project has played a key role in this venture. This research brought information concerning new biological targets that could possibly be targeted by new drugs. We have already mentioned that this availability of new targets was one of the triggers for the development of combinatorial chemistry. The fact that combinatorial chemistry companies are established exclusively for research aimed at specific genetic targets (for example involved in cancer), clearly underlines the connection between biotechnology and combinatorial chemistry.

The second connection between biotechnology and combinatorial chemistry is more important for the argument we want to make later-on in this article. Combinatorial chemistry has actually grown out of the success of one the basic technologies of biotechnology, namely molecular biology. Combinatorial chemistry only came about after molecular biology became a discipline in its own right about 25 years ago. In fact, the first generation of combinatorial libraries focused largely on peptides and oligonucleotides, because of the existence of automated, nucleid acid and peptide synthesisers/analysers. Biotechnological research was an important driver for the development of this equipment. Since then, the focus in combinatorial chemistry has shifted towards organic materials for drug design, peptides are far from ideal as an oral drug due to availability considerations.

Why is it important to point out that combinatorial chemistry has grown out of biotechnological techniques? Recent publications reveal that by far the majority of combinatorial chemistry companies are located in the USA (40-45 companies) as compared to Europe (1-2 companies) This fact can certainly not be explained by the weakness of European chemical industry, as it is traditionally very strong. Though there is no scientific research on this issue yet, the connection mentioned above between biotechnology and combinatorial chemistry suggests another explanation. The leading position of the USA in biotechnology and the far greater number of small biotechnology firms might have been the decisive factor also giving the USA the lead in combinatorial chemistry. We might observe here a 'second generation effect' for Europe's widely acknowledged weak position in biotechnology. This is all the more severe, since combinatorial chemistry can very well grow out to a new important high-tech sector. Certainly if we take into account that other advanced technologies as software and robotics are closely connected to it and that it is moving into several fields of application.

Europe's answer to USA driven trends

If combinatorial chemistry is a future core technology for pharmaceutical companies then European companies cannot afford to lag behind. The European private sector has responded accordingly. Besides starting its own activities, European companies have been active in acquiring USA based combinatorial chemistry firms. To date the take-over of Affymax, a leader in combinatorial chemistry, by pharmaceutical company Glaxo for $533 million is the largest of these acquisitions. In the agrochemicals fields forms of co-operation are being established between small combinatorial firms and large corporations, in the form of either acquisitions or target driven deals.

Box 1 Combinatorial Techniques

Combinatorial Chemistry uses different approaches to synthesize large amounts of compounds, that can subsequently be screened by rapid screening techniques. One of the most important ways of synthesising a combinatorial library (collection of compounds) is the split and mix synthesis, which we explain in more detail following the figure.

FIGURE 1. FIGURE SPLIT AND MIX COMBINATORIAL SYNTHESIS

I. In an array of separate reaction vessels, a carrier material ('resin') is present. On each carrier material, a different chemical building block is attached (in the figure: A, B, C, etc.

II. The second building block is added, G

III. The resulting compounds of step B are mixed and then split into three separate reaction vessels.

IV. Three different building blocks are added: H, I, J. The result is 18 different compounds.

It is important to note that in general, chemists do not set out from just any type of molecule fragments. If they seek a novel lead, they will start with a broad selection of interesting building blocks to combine them to a broad library. If, however, the purpose is to optimize a lead already there, they will create a more focused library, composed of building blocks closely related to the already established lead. Both approaches, lead creation and optimization, are feasible with combinatorial chemistry.

Huge amounts of potential drug candidates requires also techniques that facilitate rapid activity-screening of the compounds. Techniques such as High Throughput Screening make it possible to screen the activity of compounds in a limited amount of time.

With combinatorial chemistry and HTS, a number of automation and computation techniques have co-evolved, that facilitate the handling of large amounts of (data about) substances. For example in analytical chemistry, changes were needed to be able to assess the possible activity of compounds on a much larger scale than before. For this goal, from a cost perspective it was not possible just to multiply the use of established analytical procedures. So for this purpose, robots are developed which can automatically synthesize huge amounts of compounds as well as test them for specific activity. But automation of established procedures is not the only change in analytical technique that combinatorial chemistry has spawned. Recent developments show more advanced analytical techniques such as using a combination of microchips and chemical substances to measure activity of drug candidates.

A few European companies and institutions are involved in the formation of largely USA based consortia which share critical resources among the partners for the efficient development of new products. These developments again shows the connection with biotechnology because the formation of consortia is a development which was already going on for quite some time in biotechnology. In fact, consortia in biotechnology and in combinatorial chemistry are sometimes closely related or even overlapping. The formation of consortia is a particularly interesting phenomenon from the point of view of the future development of combinatorial chemistry. In the innovation literature it is widely acknowledged that the formation of networks is an important factor in shaping technology and innovation. The fact that at present networks are formed with USA companies at the core, will certainly influence the future landscape of combinatorial chemistry.

Policy implications

What does this all mean for policy from a European point of view? It is widely acknowledged that small ('dedicated') biotechnology firms were and are of great importance in the development of biotechnology. Europe lacks the large number of dedicated biotechnology firms as they exist in the USA. If our hypothesis about the role of biotechnology firms in the development of combinatorial chemistry is right, then the existence of dedicated biotechnology firms seems to have a double importance: not only for the development of biotechnology, but also for their technological spin-off, in this case in the form of combinatorial chemistry technology.

We should draw two lessons from this: first it underlines again very clearly the importance of a policy aimed at stimulating the emergence of dedicated biotechnology firms. However, it might not be too easy to catch up in the field of combinatorial chemistry by stimulating the emergence of dedicated biotechnology firms, because the combinatorial technology is a 'second generation technology', i.e. a spin-off from an already established sector.

The second lesson comes along with this point. Historically, biotechnology policy in Europe was understandably heavily influenced by the public debate on biotechnology and its ethical issues. Since of course the public's opinion has to be taken into account, these circumstances urged European policy makers to proceed in the field of biotechnology slowly and with caution. This might be one of the factors which contribute to Europe's present weak position in this technology. This article describes one of the possible backlashes of Europe's position on biotechnology, namely being outside of the core of developments which are a spin-off of biotechnology. This poses a difficult dilemma for the policy maker: slowing down the pace of development of one technology might mean that you cannot get in on a technology that emerges in the future, as one technology can be a spin-off of another. This can be particularly irksome if this spin-off technology is able to produce new drugs that are usually greatly appreciated by the public. There's no definite answer to solve this dilemma. However the least we can say is that the idea of investing to ensure a minimum technology base in a sector that is not widely supported by the public has at least one argument in its favour, i.e. that of keeping open the possibility of exploiting possible spin-off technologies in the future.

Keywords

combinatorial chemistry, biotechnology; technology policy

References

• Borman, S. Combinatorial Chemistry. Chemical & Engineering New. February 24, 1997.
• Cabiac, R. Combinatorial Chemistry: Tool for Innovation Breakthrough. SRI Consulting, 1997.
• Gold, L. and J. Alper. Keeping pace with genomics through combinatorial chemistry. Nature Biotechnology, volume 15, April 1997, p.297.
• Hogen, J.C. Combinatorial Chemistry in drug discovery. Nature Biotechnology, vol. 15 April 1997.
• Nature Biotechnology. Mapping a drug development revolution. Editorial. Nature Biotechnology, vol. 15 April 1997.
• Op den Brouw, P. Combinatorial Chemistry. Technieuws, 1997, Jaargang 35, nummer 4.
• Persidis, A. Combinatorial Chemistry. Nature Biotechnology, vol. 15 April 1997, p.391-392.
• Robertson, D. Combinatorial Chemistry attune to pharma needs. Chemical & Engineering New. February 24, 1997.
• Thayer, A. Monsanto to buy seed corn producer, makes agchem discovery deal. Chemical and Engineering News, January 13, 1997, p.6-7.
  

Acknowledgements

the author wishes to thank Kay Beese (IPTS) for his useful comments.

Contacts

Chris Tils, IPTS. E-mail: Contact Form

About the author

• Chris Tils is a Senior Researcher Fellow at the IPTS. He is responsible for the activities involved in the IPTS project 'Modern Biotechnology and the Greening of Industry', which forms part of the Institute's activities in environmental issues. A food engineer by training, he has worked for the Rathenau Institute, the Dutch office of Technology Assessment, in the fields of biotechnology and health care. His main research interest is the relation between policy and environmental innovation.