Computational discovery and biological evaluation of novel inhibitors targeting histone-lysine N-methyltransferase SET7

  • Bioorg Med Chem. 2020 Apr 1;28(7):115372. doi: 10.1016/j.bmc.2020.115372.
Wenjian Min  1 ,  Zeng Hou  2 ,  Fang Zhang  1 ,  Shengnan Xie  1 ,  Kai Yuan  1 ,  Haojie Dong  1 ,  Liping Wang  1 ,  Lianwen Qi  3 ,  Cheng Luo  2 ,  Hong Ding  4 ,  Peng Yang  5
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
  • 3. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 4. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
PMID: 32088124 DOI: 10.1016/j.bmc.2020.115372
Abstract

Histone-lysine N-methyltransferase SET7 emerged as a potential target for multiple cancers. In a virtual screening program used to explore new and potent inhibitors of SET7, compound 16 was discovered as a top hit with an IC50 value of 6.02 μM. A further similarity search afforded a new compound 23, which exhibited better activity against SET7 with an IC50 value of 1.96 μM. Importantly, compound 23 selectively inhibited the proliferation of MV4-11 cells. Comprehensively, compound 23 can serve as a lead for further identification and development of more potent SET7 inhibitors.

Keywords
Histone methylation; Lysine methyltransferase; SET7; Small-molecule inhibitor; Virtual screening.