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 (IC₅₀ = 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.

组蛋白赖氨酸脱甲基酶4D（KDM4D），也称为JMJD2D，在细胞增殖和存活中起重要作用，并与几种肿瘤类型有关。KDM4D已经成为治疗人类癌症的潜在靶标。在这里，我们报道了两种KDM4D抑制剂OWS [2-（1 H-吡唑-3-基）异烟酸]和10r（5-羟基-2-甲基吡唑并[1,5-a]吡啶[3， （2-e]嘧啶-3-腈），均测定为2.0。OWS是一种新发现的KDM4D抑制剂（IC ₅₀  = 4.28μM ），该化合物的关键药效​​团通过复杂的结构得以证实。化合物10r是我们之前报告的KDM4D抑制剂。为了更详细地阐明结合模式，确定了晶体结构，比较分析显示了以前从未观察到的独特相互作用。总体而言，我们的数据为合理设计提供了新的结构见解，并为优化KDM4D抑制剂提供了机会。