Liu Jiuyang, Li Fudong, Bao Hongyu, Jiang Yiyang, Zhang Shuya, Ma Rongsheng, Gao Jia, Wu Jihui, Ruan Ke
Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
FEBS J. 2017 Apr;284(7):1082-1095. doi: 10.1111/febs.14041. Epub 2017 Mar 16.
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 Å 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.
Structural data are available in the PDB under the accession numbers 5H1T, 5H1U, and 5H1V.
含三联基序蛋白24（TRIM24）与多种癌症密切相关，最近一项研究表明TRIM24的溴结构域对于致死性去势抵抗性前列腺癌的增殖至关重要。在此，我们利用基于核磁共振片段筛选的方法鉴定出三种TRIM24溴结构域的新型抑制剂。两种新型抑制剂与TRIM24溴结构域复合物的晶体结构显示，水桥相互作用网络与已知苯并咪唑酮抑制剂的网络以相同方式保守。有趣的是，一种新型抑制剂弹头处的极性取代使整个配体向TRIM24溴结构域内侧口袋内拉动约2 Å，因此呈现出与其他已知溴结构域配体显著不同的结合模式。这种模式为进一步从苗头化合物向TRIM24溴结构域新型抑制剂的先导化合物优化提供了有用的途径。
结构数据可在蛋白质数据库（PDB）中获取，登录号为5H1T、5H1U和5H1V。
