Screening
activities undertaken in-house in 2011, relative to 2008. This shows that in-house screening under- taken had only significantly increased since 2008 with respect to selectivity profiling against a panel of ion channel targets using both membrane poten- tial dyes and other technique(s). In-house screening undertaken had remained essentially unchanged with respect to screening of lead compounds against other specific ion channel targets and the primary screening of ion channels with diversity libraries. All other ion channel activities undertak- en in-house have declined, with this being most pronounced for safety assessment of development candidates against specific ion channels liabilities.
Outsourced ion channel testing today Most survey respondents still prefer not to out- source ion channel testing, but to run it in-house today. In the case of primary screens/HTS and sec- ondary screens the majority of respondents pre- ferred to run these assays in-house (73% and 72% respectively). In the case of safety assessment (non- compliant) assays and compound profiling assays most respondents prefer to run these assays in- house (49% and 44% respectively). Safety assess- ment (compliant) assays were the only ion channel testing activity where the majority (52%) prefer to outsource (Figure 5).
Where hERG testing is initiated The stage in the drug discovery/development process where the majority (44%) of survey respondents begin hERG liability testing was hits- to-leads (lead optimisation). This was followed by secondary screening (20% deploying); compound profiling (15% deploying); primary screening/HTS (13% deploying); and then safety assessment (non- compliant) (only 9% deploying) (Figure 6).
Main assay technologies used to study ion channel targets
The main assay technologies used by survey respondents in house to study ion channel targets in drug discovery in 2005 and 2011 are presented in Figure 4 and 5 respectively. In 2005 manual patch-clamping was used by most survey respon- dents in safety assessment (eg hERG compliant assays), therapeutic areas (target identification/val- idation) and compound profiling. Automated patch-clamping (APC) was used by most survey respondents in early non-compliant hERG liability testing, hits-to-leads (Lead optimisation) and sec- ondary screening. Fluorescence membrane poten- tial assays were used by most survey respondents in: primary screening of focused/targeted libraries;
Drug Discovery World Fall 2011
Figure 3: Ion channel activities undertaken in-house today
Primary screening of ion channels with diversity libraries Screening of lead compounds against specific ion channel targets
Safety assessment of lead compounds against specific ion channel liabilities
Primary screening of ion channels with focused ion channel libraries
Full pre-clinical development of ion channel targets
Safety assessment of development candidates against specific ion channels liabilities
Selectivity profiling against a panel of ion channel Selectivity profiling against a panel of ion channel targets using Selectivity profiling against a panel of ion channel targets using
membrane potential dyes automated patch clamping targets using other technique(s)
59% 53% 50% 46%
40% 41% 42% 43%
36%
0% 10% 20% 30% 40% 50% 60% % Responding
© HTStec 2011
Figure 4: Changing ion channel activities undertaken in-house (2011 versus 2008)
Selectivity profiling against a panel of ion channel targets using other technique(s)
Selectivity profiling against a panel of ion channel targets using membrane potential dyes
Screening of lead compounds against other specific ion channel targets
Primary screening of ion channels with diversity libraries
Primary screening of ion channels with focused ion channel libraries
Full pre-clinical development of ion channel targets
Safety assessment of lead compounds against specific ion channel liabilities
Selectivity profiling against a panel of ion channel targets using automated patch clamping
Safety assessment of development candidates against specific ion channels liabilities
-24%
-25% -20% -15% -10% -5% 0% 5% 10% 15% 20% % Change In Normalised Use (2011 minus 2008)
© HTStec 2011
Figure 5: Ion channel testings respondents prefer to outsource today
Safety assessment (non-compliant) assays Secondary screens Primary screens/HTS
Safety assessment (compliant) assays Compound profiling assays
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% % Responding
Prefer to run in-house Prefer to outsource No preference (ie use both) © HTStec 2011 -13% -16% -18% -0.5% -5% 1% 10% 17%
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