Nie Zhe, Shi Lihong, Lai Chon, O'Connell Shawn M, Xu Jiangchun, Stansfield Ryan K, Hosfield David J, Veal James M, Stafford Jeffrey A
Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA.
Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2018 May 15;28(9):1490-1494. doi: 10.1016/j.bmcl.2018.03.083. Epub 2018 Mar 30.
Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1.
组蛋白赖氨酸去甲基化酶（KDMs）在表观遗传调控中起关键作用，KDM5A和KDM5B已被确定为潜在的抗癌药物靶点。利用已知KDM4和KDM5抑制剂的结构信息，设计了一系列有效的吡唑基吡啶。通过结构-活性关系（SAR）探索，确定了化合物33，它是一种口服有效的、对KDM5A/5B具有显著选择性的强效抑制剂。在乳腺癌细胞系ZR-75-1中，化合物33通过三甲基化H3K4水平显示出强效的细胞抑制作用。
