2. Academic Validation
  3. Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

  • Bioorg Med Chem Lett. 2015 Nov 15;25(22):5449-53. doi: 10.1016/j.bmcl.2015.06.095.
Xu-Ri Yu 1,  Yun Tang 2,  Wen-Jing Wang 1,  Sen Ji 1,  Shuang Ma 1,  Lei Zhong 1,  Chun-Hui Zhang 1,  Jiao Yang 1,  Xiao-Ai Wu 1,  Zheng-Yan Fu 1,  Lin-Li Li 3,  Sheng-Yong Yang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: ysylilinli@sina.com.
  • 4 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: yangsy@scu.edu.cn.
PMID: 26428871 DOI: 10.1016/j.bmcl.2015.06.095
Abstract

Despite a potential application of PRMT1 inhibitors in Cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 μM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 μM, 13.1 μM and 11.4 μM, respectively.

Keywords

Epigenetics; PRMT1; Protein arginine methyltransferase; Small molecule inhibitor; Structure–activity relationship.

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