Concise solid-phase synthesis enables derivatisation of YEATS domain cyclopeptide inhibitors for improved cellular uptake.

ID: ALA4834482

Journal: Bioorg Med Chem

Title: Concise solid-phase synthesis enables derivatisation of YEATS domain cyclopeptide inhibitors for improved cellular uptake.

Authors: Jiang Y, Liu S, Tian G, Cheung HJH, Li X, Li XD.

Abstract: YEATS domains, which are newly identified epigenetic readers of histone lysine acetylation and crotonylation, have emerged as promising anti-cancer drug targets. We recently developed AF9 YEATS domain-selective cyclopeptide inhibitors. However, the cumbersome and time-consuming synthesis of the cyclopeptides limited further structural derivatisation and applications. Here, we reported a concise method for the solid-phase synthesis of the cyclopeptides, which substantially reduced the amount of time required for the preparation of the cyclopeptides and led to a higher overall yield. Moreover, this new synthetic route also allowed further derivatisation of the cyclopeptides with various functional modules, including fluorescent dye and cell-penetrating peptide. We demonstrated that the conjugation of the cyclopeptide with cell-penetrating peptide TAT led to a significantly increased cellular uptake.

CiteXplore: 34364221

DOI: 10.1016/j.bmc.2021.116342

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