2. Academic Validation
  3. Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening

Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening

  • J Med Chem. 2015 Oct 22;58(20):8166-81. doi: 10.1021/acs.jmedchem.5b01154.
Fanwang Meng 1 2,  Sufang Cheng 3,  Hong Ding 2,  Shien Liu 2,  Yan Liu 2,  Kongkai Zhu 2,  Shijie Chen 2,  Junyan Lu 2,  Yiqian Xie 2,  Linjuan Li 2 4,  Rongfeng Liu 5,  Zhe Shi 5,  Yu Zhou 3,  Yu-Chih Liu 5,  Mingyue Zheng 2,  Hualiang Jiang 2 4,  Wencong Lu 1,  Hong Liu 3,  Cheng Luo 2
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Sciences, Shanghai University , Shanghai 200444, China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 School of Life Science and Technology, ShanghaiTech University , Shanghai 200031, China.
  • 5 Shanghai ChemPartner Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, China.
PMID: 26390175 DOI: 10.1021/acs.jmedchem.5b01154
Abstract

Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes' abnormal expression or activity has been noted in several human cancers. Within this context, SET domain-containing (lysine methyltransferase) 7 (SET7, also called KMT7, SETD7, SET9) is of increasing significance due to its diverse roles in biological functions and diseases, such as diabetes, cancers, alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In this study, DC-S100, which was discovered by pharmacophore- and docking-based virtual screening, was identified as the hit compound of SET7 inhibitor. Structure-activity relationship (SAR) analysis was performed on analogs of DC-S100 and according to the putative binding mode of DC-S100, structure modifications were made to improve its activity. Of note, compounds DC-S238 and DC-S239, with IC50 values of 4.88 and 4.59 μM, respectively, displayed selectivity for DNMT1, DOT1L, EZH2, NSD1, SETD8, and G9a. Taken together, DC-S238 and DC-S239 can serve as leads for further investigation as SET7 inhibitors and the chemical toolkits for functional biology studies of SET7.

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