DECS Structural Chemistry, AstraZeneca, Waltham, MA 02451, USA.
Structure. 2011 Sep 7;19(9):1262-73. doi: 10.1016/j.str.2011.06.011. Epub 2011 Jul 21.
Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.
蛋白赖氨酸甲基转移酶是表观遗传信号的重要调节剂。这些酶催化供体甲基从 S-腺苷甲硫氨酸转移到组蛋白上特定的赖氨酸接受体，导致染色质结构和转录调控的变化。这些酶还甲基化非组蛋白蛋白底物，揭示了另一种调节细胞生理的机制。致癌蛋白 SMYD2 抑制肿瘤抑制蛋白 p53 和 Rb 的功能活性，使其成为有吸引力的药物靶点。在这里，我们报告了从高通量化学筛选中发现的强效和选择性 SMYD2 抑制剂 AZ505 的发现。我们还展示了 SMYD2 与 p53 底物和产物肽的晶体结构，特别是与 AZ505 形成复合物的结构。这种底物竞争性抑制剂结合在 SMYD2 的肽结合槽中。这些结果对 SMYD2 抑制剂的开发具有重要意义，并表明针对该靶标的新型治疗方法具有潜力。
