Zhang Jing, Qian Kun, Yan Chunli, He Maomao, Jassim Brenson A, Ivanov Ivaylo, Zheng Yujun George
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, United States.
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia 30302, United States.
Medchemcomm. 2017 Feb 1;8(2):440-444. doi: 10.1039/C6MD00573J. Epub 2017 Jan 3.
Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series of diamidine compounds with varied lengths in the middle alkyl linker for PRMT1 inhibition. Decamidine (), which possesses the longest linker in the series, displayed 2- and 4- fold increase in PRMT1 inhibition (IC = 13 μM), as compared with furamdine and stilbamidine. The inhibitory activity toward PRMT1 was validated by secondary orthogonal assays. Docking studies showed that the increased activity is due to the extra interaction of the amidine group with the SAM binding pocket, which is absent when the linker is not long enough. These results provide structural insights into developing the amidine type of PRMT1 inhibitors.
蛋白质精氨酸甲基转移酶1（PRMT1）是精氨酸甲基化动态调节的关键因子。其失调和异常表达与多种病理状况有关，大量证据表明抑制PRMT1具有显著的治疗价值。在此，我们报道了一系列在中间烷基连接体长度不同的双脒化合物用于抑制PRMT1的修饰。癸脒（）在该系列中具有最长的连接体，与呋喃脒和stilbamidine相比，其对PRMT1的抑制作用（IC = 13 μM）提高了2倍和4倍。通过二级正交试验验证了对PRMT1的抑制活性。对接研究表明，活性增加是由于脒基与SAM结合口袋的额外相互作用，而当连接体不够长时则不存在这种相互作用。这些结果为开发脒类PRMT1抑制剂提供了结构上的见解。
