Identification of novel EZH2 inhibitors through pharmacophore-based virtual screening and biological assays.
Polycomb repressive complex 2 (PRC2) acts as a primary writer for di- and tri-methylation of histone H3 at lysine 27. This protein plays an essential role in silencing gene expression. Enhancer of zeste 2 (EZH2), the catalytic subunit of PRC2, is considered as a promising therapeutic target for cancer. GSK126, a specific inhibitor of EZH2, is undergoing phase I trials for hypermethylation-related cancers. In addition, many derivatives of GSK126 are also commonly used in laboratory investigations. However, studies on the mechanism and drug development of EZH2 are limited by the absence of structural diversity of these inhibitors because they share similar SAM-like scaffolds. In this study, we generated a pharmacophore model based on reported EZH2 inhibitors and performed in silico screenings. Experimental validations led to the identification of two novel EZH2 inhibitors, DCE_42 and DCE_254, with IC50 values of 23 and 11μM, respectively. They also displayed significant anti-proliferation activity against lymphoma cell lines. Thus, we discovered potent EZH2 inhibitors with novel scaffold using combined in silico screening and experimental study. Results from this study can also guide further development of novel specific EZH2 inhibitors.
College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 210418, China.
Yunlong
Y
Wu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Junchi
J
Hu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China.
Hong
H
Ding
Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Limin
L
Chen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China.
Yuanyuan
Y
Zhang
Shanghai ChemPartner Co., Ltd, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Rongfeng
R
Liu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Pan
P
Xu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China.
Daohai
D
Du
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Wenchao
W
Lu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China.
Jingqiu
J
Liu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China.
Yan
Y
Liu
Shanghai ChemPartner Co., Ltd, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Yu-Chih
YC
Liu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China.
Junyan
J
Lu
Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: med-zhangjin@vip.sina.com.
Jin
J
Zhang
College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 210418, China. Electronic address: yao99cn@sit.edu.cn.
Zhiyi
Z
Yao
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203, China. Electronic address: cluo@simm.ac.cn.
Cheng
C
Luo
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
Computational drug design; EZH2; Epigenetics; PRC2; Pharmacophore-based virtual screening