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.

YEATS 结构域是新发现的组蛋白赖氨酸乙酰化和巴豆酰化的表观遗传阅读器，已成为有希望的抗癌药物靶点。我们最近开发了 AF9 YEATS 域选择性环肽抑制剂。然而，环肽的繁琐和耗时的合成限制了进一步的结构衍生化和应用。在这里，我们报道了一种简洁的环肽固相合成方法，该方法大大减少了制备环肽所需的时间，并提高了总收率。此外，这种新的合成路线还允许进一步衍生化具有各种功能模块的环肽，包括荧光染料和细胞穿透肽。