Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin, 300071, PR China.
West China Hospital, Sichuan University, Chengdu, 610041, PR China.
Biochem Biophys Res Commun. 2021 May 21;554:71-75. doi: 10.1016/j.bbrc.2021.03.083. Epub 2021 Mar 27.
Histone lysine demethylase 4D (KDM4D), also known as JMJD2D, plays an important role in cell proliferation and survival and has been associated with several tumor types. KDM4D has emerged as a potential target for the treatment of human cancer. Here, we reported crystal complex structures for two KDM4D inhibitors, OWS [2-(1H-pyrazol-3-yl)isonicotinic acid] and 10r (5-hydroxy-2-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile), which were both determined to 2.0 Å. OWS is a newly discovered KDM4D inhibitor (IC = 4.28 μM) and the critical pharmacophores of this compound are confirmed by the complex structure. Compound 10r is a KDM4D inhibitor reported by us previously. To clarify the binding mode in more detail, the crystal structure was determined and the comparison analysis revealed unique interactions that had never been observed before. Overall, our data provide new structural insights for rational design and offer an opportunity for optimization of KDM4D inhibitors.
组蛋白赖氨酸去甲基化酶 4D（KDM4D），也称为 JMJD2D，在细胞增殖和存活中发挥重要作用，与几种肿瘤类型有关。KDM4D 已成为治疗人类癌症的潜在靶点。在这里，我们报道了两种 KDM4D 抑制剂，OWS [2-(1H-吡唑-3-基)异烟酸]和 10r（5-羟基-2-甲基吡唑并[1,5-a]吡啶并[3,2-e]嘧啶-3-甲腈）的晶体复合物结构，两者均被确定为 2.0Å。OWS 是一种新发现的 KDM4D 抑制剂（IC=4.28μM），通过复合物结构证实了该化合物的关键药效团。化合物 10r 是我们之前报道的 KDM4D 抑制剂。为了更详细地阐明结合模式，确定了晶体结构，比较分析揭示了以前从未观察到的独特相互作用。总的来说，我们的数据为合理设计提供了新的结构见解，并为 KDM4D 抑制剂的优化提供了机会。
