title: Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening.
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.
authors.affiliation: Department of Chemistry, College of Sciences, Shanghai University , Shanghai 200444, China.|Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Fanwang
authors.initials: F
authors.lastname: Meng
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Sufang
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shien
authors.initials: S
authors.lastname: Liu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Kongkai
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Shijie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|School of Life Science and Technology, ShanghaiTech University , Shanghai 200031, China.
authors.forename: Linjuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Shanghai ChemPartner Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Liu
authors.affiliation: Shanghai ChemPartner Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Shanghai ChemPartner Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|School of Life Science and Technology, ShanghaiTech University , Shanghai 200031, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, College of Sciences, Shanghai University , Shanghai 200444, China.
authors.forename: Wencong
authors.initials: W
authors.lastname: Lu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000813:Anilides; D001549:Benzamides; C000604574:DC-S100; C000604575:DC-S238; C000604576:DC-S239; D013876:Thiophenes; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human