Drug Discovery
to first time users and to third world laboratories due to the absence of requirement for major capi- tal investment. This same advantage would allow a much broader application of kinetic measurements in laboratories currently hindered by throughput limitations.
Thus, issues with current methods and technolo- gies include the requirement for major capital investment, consumables costs well in excess of those for ‘traditional’ screening technologies, rela- tively low throughput, lack of flexibility, specialist skills required to run equipment and interpret the data output, lack of body of evidence for fidelity (particularly true of the newer techniques). No one technology is free or guilty of all of these issues, as summarised in Table 5.
To enable a much wider use of kinetics in early project decision making what would an ideal technology look like? So here’s the challenge to innovators and vendors. We want to be able to generate kinetic data on the confirmed hits from HTS (so for a HTS of 1 mil- lion entities that is 1,000-10,000 compounds depending on selected hit threshold – typically 0.1- 1%), and on all compounds synthesised in response to the HTS hits for all projects (ie lead seeking phase of a project), and on all members of a fragment library. Where we have a project that has a clear need for a definite kinetic profile (eg slow off for a long lasting bronchodilator) we want to conduct screening of large subsets or even of the whole file in kinetic format. Therefore, we would like a simple (any bio-scientist can do it), cost- effective (no more expensive than conventional screening technologies, say, $0.1 per data point) and reasonably high throughput (>10,000 data points per day – remember that each compound may require multiple data points!), assay technolo- gy to help us to achieve this. And we would like to be able to attempt this without recourse to special- ist instrumentation requiring high capital outlay, and to be compatible with current compound stor- age formats. Is that too much to ask?
DDW
Dr Wilma Keighley is an independent consultant working with biotech and academia to help design, develop and position their output for use within big Pharma. She has a strong record of success in helping gain financial support for research projects from UK and European funding bodies, a typical example of which would be BBSRC follow on funding which emphasises the commercial poten- tial of research. Before her independent work in
Drug Discovery World Summer 2011
2009, Wilma was Senior Director for New Technologies at Pfizer’s European research head- quarters leading a team responsible for identifying, assessing and implementing new methods to broaden scope and improve screening efforts. For this she built on her previous experience forming and leading a compound profiling department tasked with supporting all projects at the site with in vitro potency and selectivity data. Most impor- tantly, her team pioneered the use of frozen cells to support primary screening and innovative combi- nations of automation and manual effort to max- imise flexibility in compound management and screening. With experience in Lean and 6-sigma methodologies, Wilma has been responsible for improving cost-effectiveness in early drug discov- ery across a number of assignments including assay development, compound profiling, high through- put screening and compound management.
www.wilmakeighleyconsulting.co.uk
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J.Cardiovasc.Pharmacol., 12, Suppll.6, S144. 6 Napier, C et al (2005). Biochem. Pharmacol., 31, 163- 72. 7 Gradman, AH (2002). J. Human Hypertension 16, S9- S16. 8 Markgren, P-O et al (2002).
J.Med.Chem., 45, 5430-5439. 9 Disse, B et al (1999) Life Sci., 64, 457-464. 10 Noorda, JA van et al (2000). Thorax 55, 289-294. 11 Elg, M et al (1997). Thromb.Haemost., 78, 1286- 1292. 12 Geitmann, M et al (2006).
J.Med.Chem.,49, 2367-2374. 13 Comley, J. (2008). Drug Discovery World Fall edition, 28-49. 14 Boettcher, A et al (2010). .J Biomol. Screen. 15, 1029-41. 15 Rich, L and Myszka, DG (2010). J. Mol. Recognit. 23, 1- 64. 16 Rich, RL et al (2010). Anal. Biochem., 407, 270-277. 17 Navratilova, I et al (2011). ACS Med. Chem. Lett., Article ASAP DOI:10.1021/ m/2000017. 18 Dautzenberg, FM and Naysari, S (2005). Pharmacol., 75, 21-29. 19 Keith, RA et al (1989). JPET., 248, 240-248. 20 Gonsiorek, W et al (2007). JPET., 322, 477-485.
Other references Abbas, A et al (2011). Biosens. Bioelectron., 26, 1815-1824. Navratilova, I and Hopkins AL (2010). ACS Med. Chem. Letts 1, 44-48.
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