Stapled peptides are drawing increased attention in drug discovery and development due to their significantly improved therapeutic profile. To date, the number of reactions that allow “peptide stapling” is limited and most require the use of non-natural amino acids. Therefore, new methodologies to access these biologically relevant molecules are of great need. Here, we report a new synthetic approach for the one-pot chemoselective solid phase synthesis of all hydrocarbon bis-thioether stapled peptides. In addition, we also report the application of these methodology to developing the first inhibitors of the SANT1L-SBD domain of the master transcriptional regulator EZH2, a histone methyl transferase subunit of the polycomb repressive complex 2 of proteins, highly associated with development and progression of several forms of cancer.

Solid phase synthesis of all hydrocarbon bis-thioether stapled peptides: Application to developing new inhibitors of the master transcriptional regulator EZH2

254th National Meeting (2017)

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