Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL
Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL
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苯并[d]恶唑-2(3H)-酮衍生物的鉴定和表征，作为染色结构域蛋白 CDYL 的第一个有效且选择性的小分子抑制剂。
DOI：
10.1016/j.ejmech.2019.111656
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发表时间：
2019
影响因子：
6.7
通讯作者：
Zhang Liangren
中科院分区：
文献类型：
--
作者：
Yang Lixin;Liu Yongqing;Fan Minghua;Zhu Guiwang;Jin Hongwei;Liang Jing;Liu Zhenming;Huang Zhuo;Zhang Liangren
组蛋白翻译后修饰（PTM）的表观遗传“读者”的化学探针已成为其靶蛋白在生理和病理学中的机制和功能研究的有力工具。然而，只有有限的“阅读器”探针已经开发，这限制了我们对这些大分子及其在细胞或动物中的作用的理解。在这里，我们报告了一种结构导向的方法来开发和表征苯并[d]恶唑-2（3 H）-酮类似物作为第一个有效的和选择性的小分子抑制剂的chromodomain Y样（CDYL），组蛋白甲基赖氨酸阅读器蛋白。通过分子对接和动力学模拟研究了CDYL的色域与修饰肽模拟物之间的结合构象，为后续从Specs化学文库中虚拟筛选数十个经SPR技术验证的匹配序列（KD值为271.1 μM ~ 5.4 μM）提供了便利。进一步设计和合成了43个化合物，有助于解释导致发现新的小分子CDYL抑制剂的构效关系（SAR）。化合物D 03（KD：0.5 μM），并在其他染色结构域蛋白中显示出优异的选择性，包括CDYL 2（>140倍）、CDY 1（未观察到结合）和CBX 7（>32倍）。此外，我们证明D 03以剂量依赖性方式与内源性CDYL结合，并干扰CDYL在染色质上的募集，导致其靶基因的转录去抑制。结果表明，D 03通过抑制CDYL促进海马和皮层神经元树突的发育和分支。本研究不仅首次发现了CDYL的选择性小分子抑制剂，而且为干预表观遗传机制中生物大分子的动力学性质提供了新的化学工具。
Chemical probes of epigenetic ‘readers’ of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in physiology and pathology. However, only limited ‘reader’ probes have been developed, which restricted our understanding towards these macromolecules and their roles in cells or animals. Here, we reported a structure-guided approach to develop and characterize benzo [d]oxazol-2(3H)-one analogs as the first potent and selective small-molecule inhibitors of chromodomain Y-like (CDYL), a histone methyllysine reader protein. The binding conformation between the chromodomain of CDYL and the modified peptidomimetics was studied via molecular docking and dynamic simulations, facilitating subsequent virtual screening of tens of hits from Specs chemical library validated by SPR technique (KDvalues: from 271.1 μM to 5.4 μM). Further design and synthesis of 43 compounds helped to interpret the structure-activity relationship (SAR) that lead to the discovery of novel small-molecule inhibitors of CDYL. CompoundD03(KD: 0.5 μM) was discovered and showed excellent selectivity among other chromodomain proteins, including CDYL2 (>140 folds), CDY1 (no observed binding) and CBX7 (>32 folds). Moreover, we demonstrated thatD03engaged with endogenous CDYL in a dose-dependent manner, and perturbed the recruitment of CDYL onto chromatin, resulting in transcriptional derepression of its target genes. Finally, the results showed thatD03promoted the development and branching of neurodendrites by inhibiting CDYL in hippocampal and cortical cultured neurons. This study not only discovers the first selective small-molecule inhibitors of CDYL, but provids a new chemical tool to intervene the dynamic nature of bio-macromolecules involved in epigenetic mechanism.