Cao Yaquan, Yang Pu, Yang Yingxue, Lin Zihui, Fan Zhengmin, Wei Xuliang, Yan Lijie, Li Yongchun, He Zhangxu, Ma Liying, Xu Hongde, Wu Chunli
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China.
School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, 450001, PR China.
Eur J Med Chem. 2023 May 5;251:115250. doi: 10.1016/j.ejmech.2023.115250. Epub 2023 Mar 11.
Lysine demethylase 5B (KDM5B) is a member of the Jumonji AT-rich interactive domain 1 family. Its main function is to demethylate di/trimethyl histone H3 lysine 4 and it plays a crucial role in the occurrence and development of cancer. In this study, we performed structure-based optimization of KDM5B inhibitors based on our previous work and the most active compound we synthesized was 11ad. Molecular modeling studies and thermal shift assays revealed that 11ad specifically targets KDM5B at the molecular and cellular levels. Crucially, 11ad demonstrated good pharmacokinetic properties and anti-prostate cancer activity in a xenograft model. Furthermore, unexpectedly, the specificity of 11ad for prostate cancer was found to be related to its inhibition of the phosphoinositide 3-kinase/AKT pathway. This is the first report of a KDM5B inhibitor affecting this pathway. Taken together, our findings indicate that 11ad is a novel KDM5B inhibitor that may serve as a lead compound for the development of treatments for prostate cancer.
赖氨酸去甲基化酶5B（KDM5B）是Jumonji富含AT的相互作用结构域1家族的成员。其主要功能是使二甲基/三甲基组蛋白H3赖氨酸4去甲基化，并且在癌症的发生和发展中起关键作用。在本研究中，我们基于之前的工作对KDM5B抑制剂进行了基于结构的优化，我们合成的活性最高的化合物是11ad。分子模拟研究和热位移分析表明，11ad在分子和细胞水平上特异性靶向KDM5B。至关重要的是，11ad在异种移植模型中表现出良好的药代动力学性质和抗前列腺癌活性。此外，出乎意料的是，发现11ad对前列腺癌的特异性与其对磷酸肌醇3-激酶/AKT途径的抑制作用有关。这是关于KDM5B抑制剂影响该途径的首次报道。综上所述，我们的研究结果表明，11ad是一种新型KDM5B抑制剂，可能作为开发前列腺癌治疗药物的先导化合物。
