Phenotypic screen discovery

Schreiber gave another example where he successfully employed diver-sify-oriented synthesis for the discovery of transcription factor inhibitors (Koehler, Shamji, and Schreiber, 2003). Khersonsky and coworkers linked forward chemical genetics techniques with chemical microarrays. After phenotypic screening, triazine core-containing affinity matrices as micro-arrays were used (Khersonsky et al., 2003 Khersonsky and Chang, 2004). 

Zheng, W., Thome, N., and McKew, J.C. (2013) Phenotypic screens as a renewed approach for drug discovery. Drug Discovery Today, 18, 1067-1073. 

Figure 4.1 Chemistry-driven target identification by phenotypic screening fit in the drug discovery value chain (boxed). Some discovery activities could (should, whenever possible) be prosecuted in parallel.

Chemistry plays a key role in the discovery of novel therapeutic targets to address unmet medical needs. In this chapter, we have reviewed its use and impact in the context of phenotypic screening where, in connection to cellular SAR optimization of chemical series toward more potent and selective small molecules, upon MMoA deconvolution through a diverse array of target identification techniques (Table 4.2), it positions medicinal chemistry and disease biology very favorably both to indentify leads and candidates and to validate unprecedented targets. 

Figure 10.12 Two approaches in drug discovery, (a) Phenotypic screening approach.

Phenotypic screening on these disease models is among the most exciting applications in drug discovery because these cells are able to recapitulate known pathophysiological mechanisms. As described previously, only some... 

Moffat, J.G., Rudolph, J., and Bailey, D. (2014) Phenotypic screening in cancer drug discovery past, present and future. Nature Reviews Drug Discovery, 13, 588-602. 

In the discovery phase, MMV works with around 50 partners globally and its lead generation strategy has focused on phenotypic screening against the parasite Plasmodium falciparum. In collaboration with Novartis, GlaxoSmithKline (GSK), and St Jude Children s Research Hospital, over 5 million compounds were screened and the resultant 20 000 confirmed actives placed into the public... 

This concept is illustrated schematically in Fig. 1.3 [20]. This diagram summarizes the discovery of new modulators of both cell cycle progression and viral entry. The crux of the whole concept is the observation that Nature pairs nonpeptide small molecules with relevant protein receptors, and the number of binding-site topologies for small molecule ligands across aU protein families is limited. Phenotypic screening of the library of enantiopure a,p-unsaturated-8-lactones was exceptionally successful and has identified potent modulators of the two unrelated biological processes. In one case, the compounds are inhibitors of cell... 

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