Screening
Novel drug targets from phenotypic screening
Identifying functional molecules with the potential to be developed into new therapeutics is often the sole aim of phenotypic drug discovery. However, the approach also provides valuable opportunities to uncover previously unknown, disease-specific drug receptors that can then be exploited through target- driven means. Although target deconvolution has a reputation as a major bottleneck in phenotypic drug development, advances allowing for rapid identification of specific receptors for both biologics and small molecules are increasing the pace of phenotypic drug discovery while also providing access to the significant IP generated by the discovery of novel drug targets.
P
henotypic drug discovery has enjoyed a resurgence of interest over recent years with its relative advantages and disadvantages compared to target-based methods being exten- sively discussed and debated. Traditionally, pheno- typic drug discovery focused on the use of small molecule effector libraries to induce a desired phe- notype. However, the principles of phenotypic dis- covery are now widely applied in the field of bio- logics, with several established and newly-emerg- ing strategies now being employed for antibody- based phenotypic discovery. These approaches can range from: evoking an anti-tumour antibody response through immunisation of animals with tumour tissue (as opposed to single antigen immu- nisation), through to differential panning of nor- mal/disease cells with antibody phage libraries to select molecules that meet disease-relevant func- tional endpoints1,2.
At what point is the target relevant? By following a ‘hypothesis-free’, step-wise screen- ing approach (Figure 1) it is only once a desired phenotype has been induced does the focus switch to attempting to understand the underlying mech-
Drug Discovery World Fall 2017
anism of action of the phenotypic molecule. Success at this stage can not only uncover novel receptor targets but can also validate existing tar- gets. However, with only a 10-15% chance of suc- cessfully deconvoluting the target using conven- tional methodologies, coupled with the threat of the key finding being obscured by false positive data, it is little surprise that the exercise is often approached with trepidation.
Recent developments in cDNA expression-based target deconvolution have largely overcome that hurdle, boosting the chances of finding specific receptor targets to around 70% for compatible molecules and drastically reducing false positives. Reliable and efficient target deconvolution, in turn, opens up further possibilities for phenotypic dis- covery. For example, screening the antibodies involved in the human immune response to cancer – or those present in patients that have displayed a good response to anti-cancer treatment – is now being used to identify novel and important anti- cancer drug targets.
Due to the nature of antibodies and other large molecules and the way that they have been select- ed (for example, by panning for binding to cancer
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By Dr Jim Freeth, Dr Elizabeth Kingsley and Jo Soden
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