Screening
Figure 6: Where respondents begin hERG liability testing
Primary screening/HTS 13%
Safety assessment (non-compliant) 9%
Hits-to-leads
(lead optimisation) 44%
Compound profiling 14%
Secondary screening 20%
© HTStec 2011
Figure 7: Technologies used to study ion channels in drug discovery areas in 2005
Therapeutic area (target identification/validation) Assay development
Primary screening of full diversity libraries Primary screening of focused/targeted libraries
Secondary screening Hits-to-leads (Lead optimisation) Compound profiling Early non-compliant hERG liability testing Safety assessment (eg hERG compliant assays)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% % Responding
Manual patch-clamp
Fluorescence-based ion flux assays Membrane binding assays Field stimulation (eVIPR)
© HTStec 2011
Figure 8: Technologies used to study ion channels in drug discovery areas in 2011
Therapeutic area (target identification/validation) Assay development
Primary screening of full diversity libraries Primary screening of focused/targeted libraries
Secondary screening Hits-to-leads (Lead optimisation) Compound profiling Early non-compliant hERG liability testing Safety assessment (eg hERG compliant assays)
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% % Responding
Manual patch-clamp
Fluorescence-based ion flux assays Membrane binding assays Field stimulation (eVIPR)
© HTStec 2011 Automated patch-clamp (APC
Fluorescence polarisation binding assay Rubidium flux assays Other technique
Fluorescence membrane potential assays FRET-based membrane potential assays Oocytes
Will APC systems ever be used in primary screening? In Figures 7 and 8 were see that primary screening of full diversity libraries for ion channel activity is still mainly done by fluorescence membrane potential assays and fluorescence-based ion flux assays. Which raises the question under what cir- cumstances would survey respondents consider using APC systems for primary screening of 100,000 to 1 million compounds. Respondents’ views on this are summarised in Figure 6. The
48 Drug Discovery World Fall 2011 Automated patch-clamp (APC
Fluorescence polarization binding assay Rubidium flux assays Other technique
Fluorescence membrane potential assays FRET-based membrane potential assays Oocytes
Changes in ion channel screening metrics over the past few years Table 1 reports the primary ion channel screening metrics we have collected since 2004. The absence of a few years reflects the fact we did not collect comparable data in those years. In large pharma labs the median number of ion channel screens was four in 2004 and 2005, peaking at five in 2007 and then declining to three in 2011. This trend is roughly mirrored by the median number of data points per screen which rose from 250,000- 500,000 in 2005 to peak at 500,000-1 million in 2007 and 2008, to decline back to 250,000- 500,000 in 2009 and 2011. In small/medium phar- ma and biotech labs the median number of ion channel screens was two in 2004, peaking at three in 2005 and 2007, and then declined back to two in 2008, 2009 and 2011. This trend was again roughly mirrored by the median number of data points per screen which rose from 50,000-100,000 in 2004 to peak at 100,000-250,000 in 2005 and 2007, to decline back to 50,000-100,000 in 2008, and then further declined to 10,000-50,000 in 2009 and 2011.
primary screening of full diversity libraries; and assay development (Figure 7). In 2011 manual patch-clamping was now used by most survey respondents in safety assessment (eg hERG compli- ant assays) and therapeutic areas (target identifica- tion/validation) only. Automated patch-clamping (APC) was now used by most survey respondents in early non-compliant hERG liability testing, com- pound profiling, hits-to-leads (lead optimisation), secondary screening, primary screening of focused/targeted libraries and assay development. Fluorescence-based ion flux assays were used by most survey respondents in primary screening of full diversity libraries. 2011 also saw the emer- gence of membrane binding assays, and to a lesser extent fluorescence polarisation binding assays, particularly for early non-compliant hERG liabili- ty testing (Figure 8).
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