Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents

被引：15

作者：

Zhou, Qifan ^{[1
]}

Jia, Lina ^{[2
]}

Du, Fangyu ^{[1
]}

Dong, Xiaoyu ^{[2
]}

Sun, Wanyu ^{[2
]}

Wang, Lihui ^{[2
]}

Chen, Guoliang ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drugs Design & Discovery, Minist Educ, Sch Pharmaceut Engn, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China

[2] Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China

来源：

NEW JOURNAL OF CHEMISTRY | 2020年 / 44卷 / 06期

基金：

中国国家自然科学基金;

关键词：

HISTONE METHYLTRANSFERASE EZH2; CANCER; IDENTIFICATION; OPTIMIZATION; DISCOVERY; RECEPTOR; KETONES; POTENT;

D O I：

10.1039/c9nj04713a

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Zeste enhancer homolog 2 (EZH2) is highly expressed in various malignant tumors, which could silence tumor suppressor genes via trimethylation of H3K27. Herein was first reported a novel series of pyrrole-3-carboxamide derivatives carrying a pyridone fragment as EZH2 inhibitors. By combining computational modeling, in vitro cellular assays and further rational structure-activity relationship exploration and optimization, compound DM-01 showed powerful inhibition towards EZH2. DM-01 was found to have significant ability to reduce the cellular H3K27me3 level in K562 cells in the Western blot test. Meanwhile, our data showed that knockdown EZH2 in A549 cells resulted in a decrease of cell sensitivity to DM-01 at 50 and 100 mu M. DM-01 could also increase the transcription expression of DIRAS3 in a dose-dependent manner, a tumor suppressor in the downstream of EZH2, suggesting it was worth investigating further as a lead compound.

引用

页码：2247 / 2255

页数：9

共 31 条

[1] EZH2 Promotes Malignant Phenotypes and Is a Predictor of Oral Cancer Development in Patients with Oral Leukoplakia [J].

Cao, Wei ;

Younis, Rania H. ;

Li, Jiang ;

Chen, Haiyan ;

Xia, Ronghui ;

Mao, Li ;

Chen, Wantao ;

Ren, Hening .

CANCER PREVENTION RESEARCH, 2011, 4 (11) :1816-1824

[2] EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-β-Catenin Signaling [J].

Chang, Chun-Ju ;

Yang, Jer-Yen ;

Xia, Weiya ;

Chen, Chun-Te ;

Xie, Xiaoming ;

Chao, Chi-Hong ;

Woodward, Wendy A. ;

Hsu, Jung-Mao ;

Hortobagyi, Gabriel N. ;

Hung, Mien-Chie .

CANCER CELL, 2011, 19 (01) :86-100

[3] Molecular field technology applied to virtual screening and finding the bioactive conformation [J].

Cheeseright, Tim ;

Mackey, Mark ;

Rose, Sally ;

Vinter, Andy .

EXPERT OPINION ON DRUG DISCOVERY, 2007, 2 (01) :131-144

[4] Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis [J].

Gardner, Eric E. ;

Lok, Benjamin H. ;

Schneeberger, Valentina E. ;

Desmeules, Patrice ;

Miles, Linde A. ;

Arnold, Paige K. ;

Ni, Andy ;

Khodos, Inna ;

de Stanchina, Elisa ;

Thuyen Nguyen ;

Sage, Julien ;

Campbell, John E. ;

Ribich, Scott ;

Rekhtman, Natasha ;

Dowlati, Afshin ;

Massion, Pierre P. ;

Rudin, Charles M. ;

Poirier, John T. .

CANCER CELL, 2017, 31 (02) :286-299

[5] Hallmarks of Cancer: The Next Generation [J].

Hanahan, Douglas ;

Weinberg, Robert A. .

CELL, 2011, 144 (05) :646-674

[6] EZH2: An Epigenetic Gatekeeper Promoting Lymphomagenesis [J].

Heyn, Holger ;

Esteller, Manel .

CANCER CELL, 2013, 23 (05) :563-565

[7] Recent progress in developing selective inhibitors of protein methyltransferases [J].

Kaniskan, H. Umit ;

Jin, Jian .

CURRENT OPINION IN CHEMICAL BIOLOGY, 2017, 39 :100-108

[8] Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma [J].

Knutson, Sarah K. ;

Kawano, Satoshi ;

Minoshima, Yukinori ;

Warholic, Natalie M. ;

Huang, Kuan-Chun ;

Xiao, Yonghong ;

Kadowaki, Tadashi ;

Uesugi, Mai ;

Kuznetsov, Galina ;

Kumar, Namita ;

Wigle, Tim J. ;

Klaus, Christine R. ;

Allain, Christina J. ;

Raimondi, Alejandra ;

Waters, Nigel J. ;

Smith, Jesse J. ;

Porter-Scott, Margaret ;

Chesworth, Richard ;

Moyer, Mikel P. ;

Copeland, Robert A. ;

Richon, Victoria M. ;

Uenaka, Toshimitsu ;

Pollock, Roy M. ;

Kuntz, Kevin W. ;

Yokoi, Akira ;

Keilhack, Heike .

MOLECULAR CANCER THERAPEUTICS, 2014, 13 (04) :842-854

[9] Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497) [J].

Kung, Pei-Pei ;

Bingham, Patrick ;

Brooun, Alexei ;

Collins, Michael ;

Deng, Ya-Li ;

Dinh, Dac ;

Fan, Connie ;

Gajiwala, Ketan S. ;

Grantner, Rita ;

Gukasyan, Hovhannes J. ;

Hu, Wenyue ;

Huang, Buwen ;

Kania, Robert ;

Kephart, Susan E. ;

Krivacic, Cody ;

Kumpf, Robert A. ;

Khamphavong, Penney ;

Kraus, Manfred ;

Liu, Wei ;

Maegley, Karen A. ;

Nguyen, Lisa ;

Ren, Shijian ;

Richter, Dan ;

Rollins, Robert A. ;

Sach, Neal ;

Sharma, Shikhar ;

Sherrill, John ;

Spangler, Jillian ;

Stewart, Albert E. ;

Sutton, Scott ;

Uryu, Sean ;

Verhelle, Dominique ;

Wang, Hui ;

Wang, Shuiwang ;

Wythes, Martin ;

Xin, Shuibo ;

Yamazaki, Shinji ;

Zhu, Huichun ;

Zhu, JinJiang ;

Zehnder, Luke ;

Edwards, Martin .

JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (03) :650-665

[10] The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat [J].

Kuntz, Kevin W. ;

Campbell, John E. ;

Keilhack, Heike ;

Pollock, Roy M. ;

Knutson, Sarah K. ;

Porter-Scott, Margaret ;

Richon, Victoria M. ;

Sneeringer, Chris J. ;

Wigle, Tim J. ;

Allain, Christina J. ;

Majer, Christina R. ;

Moyer, Mikel P. ;

Copeland, Robert A. ;

Chesworth, Richard .

JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (04) :1556-1564

← 1 2 3 4 →