Design, synthesis and activity evaluation of quinolinone derivatives as EZH2 inhibitors

被引：2

作者：

Cai, Jin ^{[1
]}

You, Haoyuan ^{[1
]}

Qin, Xintong ^{[1
]}

Wang, Yuhong ^{[1
]}

Li, Wei ^{[1
]}

机构：

[1] Southeast Univ, Sch Chem & Chem Engn, Nanjing 211189, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 105卷

关键词：

EZH2; inhibitor; PRC2; Quinolinone derivatives; Anti-tumor; HISTONE METHYLTRANSFERASE; PRC2; DISCOVERY; THERAPY; POTENT;

D O I：

10.1016/j.bmcl.2024.129726

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The enhancer of zeste homologue 2 (EZH2) is the core catalytic subunit of polycomb repressive complex 2, which catalyzes lysine 27 methylation of histone H3. Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9l (EZH2WT IC50 = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2WT IC50 = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.

引用

页数：8

共 23 条

[1] The molecular mechanisms and therapeutic potential of EZH2 in breast cancer [J].

Adibfar, Sara ;

Elveny, Marischa ;

Kashikova, Hadisha Sh. ;

Mikhailova, Maria Vladimirovna ;

Farhangnia, Pooya ;

Vakili-Samiani, Sajjad ;

Tarokhian, Hanieh ;

Jadidi-Niaragh, Farhad .

LIFE SCIENCES, 2021, 286

[2] Epigenetic Therapeutics: A New Weapon in the War Against Cancer [J].

Ahuja, Nita ;

Sharma, Anup R. ;

Baylin, Stephen B. .

ANNUAL REVIEW OF MEDICINE, VOL 67, 2016, 67 :73-89

[3] Structural Context of Disease-Associated Mutations and Putative Mechanism of Autoinhibition Revealed by X-Ray Crystallographic Analysis of the EZH2-SET Domain [J].

Antonysamy, Stephen ;

Condon, Bradley ;

Druzina, Zhanna ;

Bonanno, Jeffrey B. ;

Gheyi, Tarun ;

Zhang, Feiyu ;

MacEwan, Iain ;

Zhang, Aiping ;

Ashok, Sheela ;

Rodgers, Logan ;

Russell, Marijane ;

Luz, John Gately .

PLOS ONE, 2013, 8 (12)

[4] Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas [J].

Bisserier, Malik ;

Wajapeyee, Narendra .

BLOOD, 2018, 131 (19) :2125-2137

[5] An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors [J].

Bratkowski, Matthew ;

Yang, Xin ;

Liu, Xin .

SCIENTIFIC REPORTS, 2018, 8

[6] Transcriptional regulation by Polycomb group proteins [J].

Di Croce, Luciano ;

Helin, Kristian .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2013, 20 (10) :1147-1155

[7] EZH2 alterations in follicular lymphoma: biological and clinical correlations [J].

Huet, S. ;

Xerri, L. ;

Tesson, B. ;

Mareschal, S. ;

Taix, S. ;

Mescam-Mancini, L. ;

Sohier, E. ;

Carrere, M. ;

Lazarovici, J. ;

Casasnovas, O. ;

Tonon, L. ;

Boyault, S. ;

Hayette, S. ;

Haioun, C. ;

Fabiani, B. ;

Viari, A. ;

Jardin, F. ;

Salles, G. .

BLOOD CANCER JOURNAL, 2017, 7 :e555-e555

[8] PRC2 and SWI/SNF Chromatin Remodeling Complexes in Health and Disease [J].

Kadoch, Cigall ;

Copeland, Robert A. ;

Keilhack, Heike .

BIOCHEMISTRY, 2016, 55 (11) :1600-1614

[9] An inflammatory switch for stem cell plasticity [J].

Kathiriya, Jaymin J. ;

Peng, Tien .

NATURE CELL BIOLOGY, 2021, 23 (09) :928-929

[10] Discovery of EBI-2511: A Highly Potent and Orally Active EZH2 Inhibitor for the Treatment of Non-Hodgkin's Lymphoma [J].

Lu, Biao ;

Shen, Xiaodong ;

Zhang, Lei ;

Liu, Dong ;

Zhang, Caihua ;

Cao, Jingsong ;

Shen, Ru ;

Zhang, Jiayin ;

Wang, Dan ;

Wan, Hong ;

Xu, Zhibin ;

Ho, Ming-Hsun ;

Zhang, Minsheng ;

Zhang, Lianshan ;

He, Feng ;

Tao, Weikang .

ACS MEDICINAL CHEMISTRY LETTERS, 2018, 9 (02) :98-102

← 1 2 3 →