Serenex turns drug discovery back to front

In an industry where innovation is king, the North Carolina based pharma company claims this novel, seemingly backwards approach has worked well for it, and often against targets that are impossible or difficult to screen against. Traditionally, drug developers will first choose a druggable protein target and then screen it against a library of small molecules. The ones that bind to the target best ('hits') are then optimised and one or more are chosen for further tests ('leads'). "Instead of picking the target first, we run a huge parallel screen to choose that target,"​ explained Dr Steven Hall, head of R&D at Serenex, at last month's drug Discovery and Development of innovative Therapeutics (DDT) conference, US. ​"This is a different approach to drug discovery that has resulted in the identification of a number of highly selective, highly potent [heat shock protein 90] Hsp90 inhibitors which are now in the clinic." ​ Using a specially designed affinity media, proteins are reversibly 'caught' from virtually any tissue or cell culture source. To reduce the number of targets in the screen, Hall explained that the company decided to focus on those which bind to the small molecule, purine. Since this superfamily of proteins includes kinases, reductases, transferases, synthetases, dehydrogenases, and chaperone (heat shock) proteins, the decision has not focussed the company's research in too narrow an area. A number of potential drug compounds are then added to the affinity media to which up to 2000 proteins are bound. Since each small molecule competes with the affinity media for the protein binding site, only those proteins that bind more strongly to a small molecule become detached. These can then be collected and identified. "In essence, we can search through the thousands of proteins in a particular tissue and very rapidly identify only the few protein targets to which a particular compound has affinity,"​ according to the company. Hsp90 regulates the folding and degradation of other proteins, including those involved in cancer, inflammatory diseases, fungal infection resistance, viruses and neurodegenerative diseases such as Alzheimer's. As such, Serenex has ongoing pre-clinical programs in all of these areas as well as two oncology compounds in the clinic. When the idea was executed, some 8,000 compounds were designated as hits from 2.4million, with around 100 protein targets. The targets were over a broad array of classes, not just limited to chaperone proteins. One particular Hsp90 inhibitor stood out which was then optimised to increase binding strength. The company then obtained a co-crystal structure of the compound bound to Hsp90 and elucidate its novel interactions, when compared with a natural substrate, ATP. These differences were then exploited to improve the compound even further and the resultant molecule looked structurally very different to other Hsp90 inhibitors, according to Hall. The compound, SNX-7081, is currently undergoing preclinical testing but Serenex's most advanced Hsp90 inhibitor is SNX-5422. This anticancer molecule is currently in Phase I clinical trials in an oral formulation and in preclinical testing in its intravenous form.