Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation
Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation
复制标题
具有预组织构象的环肽抑制剂选择性靶向 AF9 YEATS 结构域。
DOI：
10.1021/jacs.0c10324
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发表时间：
2020-12-23
影响因子：
15
通讯作者：
Li, Xiang David
中科院分区：
文献类型：
--
作者：
Jiang, Yixiang;Chen, Guochao;Li, Xiang David
YEATS结构域是新近发现的组蛋白赖氨酸乙酰化（Kac）和巴豆酰化（Kcr）的表观遗传“阅读器”。已发现YEATS-Kac/Kcr相互作用的故障参与人类疾病（例如癌症）的发病机制。这些发现表明，YEATS结构域是有前途的新型药物靶点。我们和其他人最近报道了YEATS结构域抑制剂的发展。尽管这些抑制剂对AF 9和ENL YEATS结构域具有普遍偏好，但靶向任一YEATS结构域的选择性抑制剂的开发具有挑战性，因为这两种蛋白质具有高度的结构相似性。在这项研究中，我们确定了一个近端网站以外的酰基赖氨酸结合口袋，可以区分AF 9叶ATS从ENL叶ATS。通过构象上预组织的环肽组合靶向酰基赖氨酸口袋和该额外位点使得能够选择性抑制AF 9 YEATS结构域。最具选择性的抑制剂JYX-3对AF 9 YEATS的结合亲和力比ENL YEATS高38倍。进一步的研究表明，JYX-3可以在活细胞中与AF 9结合，破坏AF 9的YEATS依赖的染色质募集，并抑制AF 9靶基因的转录。
YEATS domains are newly identified epigenetic "readers" of histone lysine acetylation (Kac) and crotonylation (Kcr). The malfunction of YEATS-Kac/Kcr interactions has been found to be involved in the pathogenesis of human diseases, such as cancer. These discoveries suggest that the YEATS domains are promising novel drug targets. We and others recently reported the development of YEATS domain inhibitors. Although these inhibitors have a general preference toward the AF9 and ENL YEATS domains, selective inhibitors targeting either YEATS domain are challenging to develop as these two proteins share a high structural similarity. In this study, we identified a proximal site outside the acyllysine-binding pocket that can differentiate AF9 YEATS from ENL YEATS. Combinatorial targeting of both the acyllysine pocket and this additional site by conformationally preorganized cyclopeptides enabled the selective inhibition of the AF9 YEATS domain. The most selective inhibitor, JYX-3, showed a 38-fold higher binding affinity toward AF9 YEATS over ENL YEATS. Further investigations indicated that JYX-3 could engage with AF9 in living cells, disrupt the YEATS-dependent chromatin recruitment of AF9, and suppress the transcription of AF9 target genes.