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Technology - Chemical Genomics In Drug Discovery

Pradeep Sharma

(This article is sponsored by The Boston Group)

There’s still debate over exactly what is meant by chemical genomics. Recently held Scivent conference “Chemical Genomics: A New Paradigm in Drug Discovery” held in Basel, Switzerland, attracted a wide range of delegates from both Big pharma and biotech, and delegates were keen to share how they were integrating their own vision of chemical genomics into drug discovery and development.

“While there is no unique definition of chemical genomics, many people agree that it is information-driven” as the VP of research & development of Aventis Pharma AG pointed out. The discovery of druglike leads has now become a major bottle neck, and while attrition is an inherent part of drug discovery, there is an urgent need to push it up front, perhaps by focusing more upon smart information based approaches rather than dealing with millions of potential drug molecules. Aventis has adopted a chemogenomics approach where the chemical / structure space of small molecules is mapped onto the biological space of drug target families. It is not dissimilar to serendipity, or chance, approach that has served the pharmaceutical industry so well in the past, but it has the advantage of using the most refined and advanced technologies.

For Hoffmann-LaRoche, chemical genomics is an emerging paradigm in drug discovery that means classifying proteins by structure and functions, then correlating them with known chemical ligands, placing the compound at the heart of the discovery process. “It is about getting as much as you can out of the compounds you have,” said the head of the discovery chemistry. The key concept is that similar compounds bind to similar targets and many compounds, such as anti-psychotics and clozapine, bind to multiple targets. It should be possible to build on and exploit this using new technology. The Hoffam-LaRoche approach is known as Roche Adapted Drug Discovery and Refinement (RADDAR), a rapid lead generation process, which has accelerated hit-to-lead time to four months, compared to the industry average of 18 months.

GPC Biotech is also trying to integrate chemical genomics into its drug discovery approach and has pioneered a technology called Reverse GenomicsTM, which involves the study of drug mechanisms of action using genomics and pretomics technologies. This differs from the usual study of disease mechanisms where phenotypes are analyzed using genomics and proteomics to lead to drug discovery. “We want to know how small molecules affect cells and animals,” said CSO of the company. The company is doing this through a new technology called LeadCodeTM, which is a modification of the yeast two-hybrid system normally used to study protein-protein interaction.

Another company, Avalon Pharmaceuticals is pioneering forward chemical genomics, that is, concentrating on the early stages of drug discovery process. In other words, company looks at the effect of small molecules upon multiple gene expression systems within the cell. So its drug discovery process involves a primary transcriptional screen, followed by hit characterization and lead selection, then lead optimization. The company has already used this approach to define hits for colorectal cancer and breast cancer and have a database of large-scale transcriptional effects of hundreds of reference compounds and novel hits.

(Pradeep Sharma has a Ph.D. in Organic Chemistry and more than nine years of experience in Pharmaceutical industry in India, Canada and the USA. His areas of research are drug discovery, combinatorial chemistry and process research and development of active pharmaceutical ingredients (API’s). )

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