Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
Eur J Med Chem. 2020 Apr 15;192:112161. doi: 10.1016/j.ejmech.2020.112161. Epub 2020 Feb 20.
KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC of 9.320 μM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC of 0.0244 μM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric cancer treatment.
KDM5B（也称为 PLU-1 和 JARID1B）是一种依赖 2-氧戊二酸和 Fe 的氧依赖酶，作为组蛋白 H3K4 去甲基酶起作用，它是作为药物靶点抑制肿瘤抑制剂表达的关键参与者。在这里，我们通过基于结构的虚拟筛选和生化筛选发现了吡唑衍生物化合物 5，其对 KDM5B 的 IC 为 9.320 μM，随后对其进行优化得到 1-(4-甲氧基苯基）-N-(2-甲基-2-吗啉丙基）-3-苯基-1H-吡唑-4-甲酰胺（27ab），这是一种有效的 KDM5B 抑制剂，其 IC 为 0.0244 μM。在 MKN45 细胞中，化合物 27ab 可以结合并稳定 KDM5B，并诱导 KDM5B 的 bona fide 底物 H3K4me2/3 的积累，同时保持 H3K4me1、H3K9me2/3 和 H3K27me2 的数量不变。进一步的生物学研究也表明，化合物 27ab 是一种有效的细胞活性 KDM5B 抑制剂，能够抑制 MKN45 细胞的增殖、伤口愈合和迁移。总之，我们的发现为 KDM5B 抑制剂的发现提供了一种新的结构，针对 KDM5B 可能是治疗胃癌的一种新的治疗策略。
