The polar warhead of a TRIM24 bromodomain inhibitor rearranges a water-mediated interaction network
The polar warhead of a TRIM24 bromodomain inhibitor rearranges a water-mediated interaction network
复制标题
TRIM24 溴结构域抑制剂的极地弹头重新排列水介导的相互作用网络
DOI：
10.1111/febs.14041
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发表时间：
2017-04-01
期刊：
影响因子：
5.4
通讯作者：
Ruan, Ke
中科院分区：
文献类型：
--
作者：
Liu, Jiuyang;Li, Fudong;Ruan, Ke
含有三个基序的蛋白24(TRIM24)与多种癌症密切相关，最近的一项研究表明，TRIM24的溴结构域对致死性去势抵抗前列腺癌的增殖是必不可少的。在这里，我们通过基于核磁共振片段的筛选确定了三个新的TRIM24溴域抑制剂。两个新的缓蚀剂与TRIM24溴结构域络合物的晶体结构表明，水桥相互作用网络与已知的苯并咪唑酮类缓蚀剂具有相同的保守方式。有趣的是，一个新的抑制剂在弹头上的极性取代将整个配体拉入TRIM24溴域的内侧口袋，从而显示出与其他已知的溴域配体显著不同的结合模式。这种模式为进一步向TRIM24溴域的新型抑制剂的点击到领先进化提供了有用的句柄。
Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors. Interestingly, the polar substitution on the warhead of one new inhibitor pulls the whole ligand approximately 2 angstrom into the inner side pocket of the TRIM24 bromodomain, and thus exhibits a binding mode significantly different from other known bromodomain ligands. This mode provides a useful handle for further hit-to-lead evolution toward novel inhibitors of the TRIM24 bromodomain.