This page contains a Flash digital edition of a book.
Screening


Figure 1


 


o 


o  


o  


o 


o  


o  o 





o  o  o  o  o  o 


o  





o  o  o 


and chemical probes as tool compounds, to reveal known targets and pathways that are active in the assay and need to be excluded. Secondary assays for these targets can then be run following the pri- mary screen. Following this triage, the remaining hits must be further classified and prioritised. This mechanistic classification can be accomplished using unsupervised multi-parameter profiling approaches such as transcriptomic, proteomic or high content analysis within the screening assay itself, or by employing more extensive phenotypic profiling across additional assays. The usefulness of these unsupervised methods is increased by cov- erage of biology and the availability of reference signatures of compounds with known mechanisms to which hits may be compared. This effort can reveal additional mechanisms or identify new assays that should be incorporated into the screen- ing funnel, and can also help support target deconvolution. Target deconvolution is an important activity that must also be considered for phenotypic dis- covery programmes. While many drugs have been approved without a known molecular target, knowledge of the target is highly valuable for the discovery of follow-up compounds, and for de- risking the potential for unexpected toxicities in vivo9. Known targets can be eliminated by testing


Drug Discovery World Fall 2017


in target-based cellular or biochemical panels, such as those established for safety pharmacology or for broad coverage of particular target classes, such as comprehensive GPCR or kinase panels. For the identification of truly novel targets, there have been advances in methods to identify targets using chemical proteomics techniques such as affinity pull down, functional genomics methods or molec- ular profiling. These can be time-consuming and resource intensive, and often multiple approaches are required. Thus, for most discovery research groups, unless the chemistry lends itself to such an effort, target deconvolution activities are only ini- tiated late in discovery. Phenotypic profiling stud- ies that leverage the use of bioactivity fingerprints across standard panels, ideally that cover a broad range of biology to classify compounds based on mechanistic similarity, can be used to prioritise candidates prior to initiating these efforts.


Future – the integration of phenotypic and target-based discovery approaches A common theme emerging from pharmaceutical research is the need for more effective integration of human biology into the drug discovery enter- prise. Years of investments in ’omics technologies that measure the cellular components of biological systems and permitting the generation of pathway


29


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72