Chemoproteomic-enabled phenotypic screening

The ID of disease-modifying, chemically accessible targets remains a central priority modern therapeutic discovery. phenotypic screening small-molecule libraries not only represents an attractive approach to identify compounds that may serve as drug leads but also serves opportunity uncover with novel mechanisms action (MoAs). However, major bottleneck screens continues be the pharmacologically relevant target(s) for interest. field chemoproteomics aims map proteome-wide interactions in complex, native systems, and has proved key technology unravel protein pharmacological modulators. In this review, we discuss application chemoproteomic methods hits investigate MoAs, specific focus on development chemoproteomic-enabled compound streamline target Quality chemical probes are powerful tools biology can new medicines (Arrowsmith et al., 2015Arrowsmith C.H. Audia J.E. Austin C. Baell J. Bennett Blagg Bountra Brennan P.E. Brown P.J. Bunnage M.E. al.The promise peril probes.Nat. Chem. 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Rep. 33: 681-708Crossref Park 2019Park Ha screening.Curr Opin Chem 50: 66-72https://doi.org/10.1016/j.cbpa.2019.02.006Crossref (11) Here, aim highlight examples coupled particular implementation specialized progression studies. generally composed (1) group interaction subset (2) reactive electrophilic photoreactive) covalent interacting tag fluorophores, biotin, click-chemistry-enabled handles) detection, enrichment, visualization (Figure 1A) (Drewes Knapp, 2018Drewes Knapp Chemoproteomics discovery.Trends Biotechnol. 36: 1275-1286Abstract (38) Parker Pratt, 2020Parker C.G. Pratt M.R. Click chemistry proteomic investigations.Cell. 180: 605-632Abstract (25) Chemoproteomic experiments performed either comparative competitive format 1B). format, probes, same under different conditions, compared. 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