Department of Chemistry, Imperial College London , South Kensington Campus, London SW7 2AZ, United Kingdom.
J Med Chem. 2013 Nov 14;56(21):8616-25. doi: 10.1021/jm401063r. Epub 2013 Oct 25.
Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between 1 and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by 1 in vitro and has implications for the activity of ETPs against these important epigenetic targets.
组蛋白赖氨酸甲基转移酶（HKMTs）是表观遗传学治疗的一个重要靶点。1（chaetocin），一种二噻唑啉酮（ETP）天然产物，已被报道为 SU(VAR)3-9 类 HKMTs 的特异性抑制剂。我们研究了 1 和功能相关类似物对 HKMT G9a 的抑制作用。我们的结果表明，只有结构独特的 ETP 核心是抑制所必需的，并且这种抑制是时间依赖性和不可逆的（在没有 DTT 的情况下），最终导致蛋白质变性。质谱数据为这种效应提供了分子基础，证明了 1 与蛋白质之间形成了共价加合物。这为 1 在体外对多种 HKMTs 的抑制观察到的选择性提供了潜在的依据，并对 ETP 针对这些重要表观遗传靶点的活性具有重要意义。
