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BioFocus e-update January 2010
A New Year, new endorsements and an alternative business model
Chris Newton, Managing Director and SVP BioFocus
Happy New Year to all our readers. 2010 will bring new opportunities and both BioFocus and its parent group, Galapagos, are ready for them. We are excited about the organisation that we have built and the comprehensive services that BioFocus can provide to our partners. In this edition, I’d like to focus upon two topics: our target discovery platform, and a third party endorsement of our library design capabilities.
Galapagos is now engaged in seven alliances with GSK, J&J, Lilly, Merck and most recently Roche. These alliances are in diverse therapeutic areas, and cover target discovery all the way through to the clinic. In all cases, the start is the identification of novel targets in a therapeutic area. It is already difficult to bring a small molecule based on known biology to the clinic. Novel targets add a whole additional level of complexity and risk. Despite protestations to the contrary, pharma remains nervous on accepting novel targets into the pipeline; results from our proprietary adenoviral knock-down (KD) technology can buttress faint hearts against that nervousness, with the proof that the first two products are now in clinical trial.
However, it is not necessary to commit to a broad target-to-the-clinic, multi-year alliance with Galapagos to access the proprietary knock-down technology. The January 2008 announced project between BioFocus and Janssen Pharmaceutica to identify novel targets for the J&J oncology division Ortho Biotech has been remarkably successful in less than two years. In this alliance, we devised complex phenotypic assays conceptualised by J&J and reduced to practice by our scientists upon which high-throughput screens of the drugable genome (using 7,000 viruses of our adenoviral library) were conducted (see: de Pril, R.; Perera, T.; Lekkerkerker, A. A high-content screen for inhibitors of cell migration in cancer metastasis using adenoviral knock-down. Biotech International. 2009, April/May issue). So confident are we that such assays will identify targets that we are prepared to run the BioFocus target discovery business on a risk-reward basis – cover our costs, and reward us when we transfer you the validated targets. Come to us with your assay ideas. For more information, contact david.fischer@glpg.com at our Leiden site.
We are always keen to see BioFocus recognised as undertaking pioneering work, and third party endorsement is worth a hundred times what we say about ourselves. A recent paper first web-published on December 1, 2009 (High-Throughput Screening To Identify Inhibitors Which Stabilize Inactive Kinase Conformations in p38α) by Simard et al. from the Chemical Genomics Centre of the Max Planck Society (J. Am. Chem. Soc., 2009, 131 (51), pp 18478–18488) has identified and demonstrated the binding mode (by X-ray crystallography) of the first reported DFG-out binding thiazole-urea compounds and reveals a new Type III binding mode for this scaffold. The BioFocus library (SFK48) that this compound came from was designed by BioFocus scientists to elicit this binding mode and has been on sale since June 2007.
BioFocus launches MDR1 transporter assay
New to our ADME offering is the MultiDrug Resistance (MDR) efflux transporter assay. Based in the Madin-Darby canine kidney strain II (MDCKII)cell line licensed from Solvo Biotechnology (Hungary), the assay provides an in vitro tool for studying the impact of this drug transporter on compound permeability to the CNS and potential drug-drug interactions at the blood brain barrier.
Monolayers of the MDCK II cell line with transfected human MDR1 gene are an excellent tool to investigate the interactions of medium to high permeability test compounds with this transporter. The effective efflux ratio between the transfected and parental cell lines is a measure of the MDR1 transporter-mediated active efflux process. The assay is offered with LC-MS/MS analysis of the test compound and complements our P-gp transporter assays based on Caco-2 cells (with and without selective transport inhibitors) and measurement of membrane bound ATPase activity.
These in vitro tools, along with our brain tissue dialysis capability, protein binding determination and measurement of ex vivo drug concentrations in brain tissue, provide an early chance to reduce development failures for CNS candidates by assessing the potential hurdles to CNS drug delivery as early as possible in the overall CNS drug development process.
Screening for accelerated hit-finding
Doris Hafenbradl, Senior Director, Biology and Natural Products
What is the best way to start a hit finding campaign? This question is frequently asked when a new target has been validated and inhibitors or modulators need to be identified. In the past, the clear answer was that the largest compound libraries available should be screened; now an evaluation of the available tools and compound libraries are mandatory in order to identify the most economic and successful strategy.
We have found that a careful evaluation of the target and also the know-how about the binding site and inhibitors in order to select a specific compound screening deck is more successful for hit discovery compared to large compound screening campaigns which are often very expensive and time consuming. From our collection of 900,000 compounds a smart screening deck can be selected using physico-chemical filters and in silico ADME tools. This filtering allows the selection of lead-like compounds, compounds which have a high chance to penetrate the blood brain barrier or other requirements which are usually dictated by the therapeutic indication.
This can be combined with tools that will be applied to various structure based approaches (e.g. docking and proprietary post-filtering techniques) if the protein structure of the target is known. Specific binding sites can then be addressed and highly focused binding motifs can be selected for screening. Even if no information about the binding site or the protein structure is known, very powerful chemoinformatics tools can be used to select compounds based on ligand structures and binding partners (e.g. GPCR ligand based pharmacophore modeling).
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At the same time, all selections are biased towards the maximum diversity to also allow for serendipity. After the HTS of the selected compounds deck (typically 20,000 to 200,000 compounds), statistical data mining and clustering methods enable the distillation of active feature information and hence the identification of active areas in chemical space even for weakly active compounds. In this BioFocus hit-finding paradigm, iterative cycles of screening are applied during a “hit-expansion” phase. Our technologies enable the detection of potentially highly active compounds from the 900,000 compound inventory, with fast turnaround rates.
Ever thought of trying something new?
Richard Gordon, Senior Director, Sales and Marketing
Ever thought of outsourcing your entire compound screening deck handling needs or having a third party look after your tissue samples? BioFocus is proud of the incredible team it has created, with scientists from diverse backgrounds (GSK, Pfizer, Merck, UCB, Roche) pooling their experiences and offering insight into drug discovery. As well as receiving ideas of projects for BioFocus to work upon, we feel confident we can suggest novel hot projects in diverse therapeutic areas for third parties. Contact richard.gordon@glpg.com.
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