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BioFocus e-update July 2010
Enhanced target class capability
Kate Hilyard, VP Biological Sciences, BioFocus
During the first half of 2010 we have enhanced our capabilities to engage in projects to discover compounds that act on ion channels, kinases, GPCRs and protein-protein interaction (PPI) targets. New research partnerships are being formed and existing ones are flourishing, through capability enhancements that include:
- placement into BioFocus of a Cellectricon Dynaflow® HT system - the first fully automated patch clamp system offering increased electrophysiology-based screening capacity, particularly for fast ligand-gated ion channels. This is the first such instrument to be sited in a CRO
- acquisition of the first to market impedance-based label-free high throughput instrument, the CellKey™ 384 from Molecular Devices, providing fully automated measurement of kinetic cellular responses for GPCR and other target classes
- arrival of a second Biacore™ instrument; the T4000 provides not only further label free capacity but also streamlines the handling of data allowing a higher throughput in protein/protein interaction assays and direct ligand binding assays
- recent agreement with Millipore which allows BioFocus to perform screening on behalf of our customers using Millipore ChemiScreen™ and PrecisION™ cell lines giving access to more tools for GPCR and ion channel discovery programs
Kinases remain a target class of particular interest to clients. BioFocus’ capability in generating libraries of compounds that yield novel hits against kinases has been externally recognised in a recent publication (Inhibitors of PIM-1 Kinase: A Computational Analysis of the Binding Free Energies of a Range of Imidazo [1,2-b] Pyridazines J. Chem. Inf. Model., 2010, 50 (3), 368–379). This publication describes recent work between BioFocus and the University of Manchester which involved compounds from BioFocus’ SoftFocus kinase targeted library SFK33. Using computational methods the binding of a selection of competitive imidazo[1,2-b]pyridazine inhibitors (with nanomolar activity) to PIM-1 kinase were analyzed. New libraries from BioFocus launched in 2010 are: our Helix Mimetic library HM02, and kinase directed libraries SFK61, SFK62, SFK63. To be launched later in the year will be FieldFocus libraries directed at GPCRs, protein-protein interaction libraries based on beta/gamma turn mimetics and further kinase directed libraries with multiple binding modes based on planer monocycles or bicycles.
Contact us for further information.
Finding a universal cure for childhood diarrheal diseases
Angus MacLeod, VP Medicinal Chemistry, BioFocus
One of the great attractions of working in a basic research CRO environment is the broad diversity of therapeutic areas and scientific challenges that are tackled. A recent example of such a program is the collaboration between BioFocus and the Institute for OneWorld Health, a not-for-profit organization seeking to bring new medicines to the developing world.
Acute secretory diarrhea is responsible for the deaths of up to 2 million children each year in the developing world. The current standard of care is a glucose/salt solution, oral rehydration therapy (ORT), which is a palliative treatment for the disease. However, the labor intensive regimen alongside a lack of symptomatic relief leads to a high level of noncompliance. The identification of an adjunct therapy to work alongside ORT, and improve time to symptomatic relief, would be of great value.
Acute secretory diarrhea is caused by an intestinal infection with vibrio cholerae resulting in the output of large volumes of watery stools. The major mechanism for this infection is the over-activation of a chloride ion channel, CFTR (cystic fibrosis transmembrane conductance regulator), present in the epithelial cells within the intestinal wall.
Working together with the Institute for OneWorld Health, we established a drug discovery program covering medicinal chemistry, biology and ADME/PK to identify and optimize compounds that inhibit chloride secretion by CFTR. This included a high throughput screen (HTS) of 750,000 compounds and extensive evaluation of novel synthesized compounds in a range of electrophysiological experimental settings. As a result of an iterative program of compound synthesis and evaluation, a range of compounds were identified that are effective in inhibiting the excessive secretion of fluid in animal models of cholera induced diarrhea.
This has resulted in the selection of compounds as potential drug development candidates for the treatment of cholera. The success of this program is a testament to the quality of science of the staff at BioFocus and their dedication towards delivering results on complex drug discovery programs.
Developments in electrophysiology-based screening technologies
Susanne Fagerlund, VP Marketing Communications, Cellectricon
The field of ion channel research has benefited greatly from the recent introduction of novel electrophysiology-based screening technologies. Cellectricon’s Dynaflow® HT is a new commercially available assay platform that combines 96 channel recording capabilities with microfluidic channel-based perfusion, integrated into a consumable recording plate.
Combining accurate voltage control with precisely defined ligand and drug application times, the new system is a flexible and powerful tool for screening of both voltage- and ligand-gated ion channels. Unlike some multichannel automated systems, the Dynaflow® HT maintains voltage-clamp recording throughout the entire experimental protocol.
Key features of the system:
- rapid compound application with switch times of 30 ms (10-90%) or less. Whilst the ability to record from voltage-gated ion channels without losing voltage control is a significant benefit, precise and rapid control of compound and ligand application provides a very clear advantage for ligand-gated ion channel research
- multiple cycles of compound application and wash-off can be done during individual experiments and maximizes the efficiency of data generation
- the ability to plan for experiments of up to four hours duration without any user intervention. This is made possible by a comprehensive software-based control system, on-board cell maintenance and preparation, automated consumable and compound plate handling plus a flexible pipette system for movement of control and drug solutions into the recording plate
- the system has a unique recording head module and the system requires exceptionally low cell consumption to run an experiment-less than 5 µl of a 100,000 cells/ml suspension is required to fill a recording plate
- each recording plate consists of 16 banks of six individual recording sites. This increases the likelihood of obtaining statistically meaningful data
During the development the instrument has been extensively tested on a variety of host cell backgrounds (including CHO, HEK, WSS1, LTK, PC 12, SH-SY5Y, TE671), and robust screening data has been generated using a variety of ligand- and voltage-gated ion channels.
Accurate quantification of compound potency and efficacy in the early stages of hit prioritization and subsequent hit-to-lead profiling should mean this instrument will have a significant role to play in driving medicinal chemistry towards efficacious and selective chemical material.
BioFocus is the first contract research organization in the world to offer electrophysiology-based screening services using the Dynaflow® HT system.
Contact us for further information.
Additional web tools to expand your knowledge
Many drug discovery projects share common ADME/PK problems and pitfalls, and our experts have developed experience of dealing with these issues. Access this knowledge, by using the new Ask the ADME expert function within the ADME / PK section.
The quality of our science is reflected in patent applications (where our scientists appear as joint inventors on client projects) and in our publications. Wherever possible, BioFocus encourages our scientists to publish, present and defend posters, and present orally at conferences. This information is freely available to you through the new Our science section.
Webinars and conferences
In May, BioFocus hosted two successful webinar events covering aspects of ADME and hit-finding utilizing in silico tools. If you would like to view the webinars, download a recording, look over the slides or review the Q&A session please click here.
Every year BioFocus sponsors and hosts seminars and conferences reporting both advances of known research and novel technologies. The event below is our next such conference and is free to attend.
Protein Kinase 2010: Signalling Success
BioFocus co-sponsors and hosts the 4th SCI RSC Symposium on Kinase Inhibitor Design. Wednesday 20 October, The Nucleus, Chesterford Research Park, Saffron Walden, Essex, CB10 1TS UK
Register for FREE
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