Discovery of novel ATAD2 bromodomain inhibitors that trigger apoptosis and autophagy in breast cells by structure-based virtual screening

被引：24

作者：

Yao, Dahong ^{[1
,2
]}

Zhang, Jin ^{[3
,4
]}

Wang, Jinhui ^{[5
]}

Pan, Dabo ^{[6
]}

He, Zhendan ^{[1
,2
]}

机构：

[1] Shenzhen Univ, Sch Pharmaceut Sci, Guangdong Key Lab Genome Stabil & Human Dis Preve, Shenzhen 518060, Peoples R China

[2] Shenzhen Univ, Shenzhen Key Lab Novel Nat Hlth Care Prod, Engn Lab Shenzhen Nat Small Mol Innovat Drugs, Innovat Platform Nat Small Mol Drugs,Hlth Sci Ctr, Shenzhen, Peoples R China

[3] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Chengdu, Peoples R China

[4] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Canc Ctr, Chengdu, Peoples R China

[5] Shenzhen Honghui Biopharmaceut Co Ltd, Shenzhen, Peoples R China

[6] Jinan Univ, Coll Pharm, Guangdong Prov Key Lab Pharmacodynam Constituents, Inst Tradit Chinese Med & Nat Prod, Guangzhou, Peoples R China

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2020年 / 35卷 / 01期

基金：

中国国家自然科学基金;

关键词：

ATAD2; breast cancer; Virtual Screening; apoptosis; autophagy; LYSINE ACETYLATION; CANCER; PROTEIN; FAMILY; ANCCA; PROGNOSIS; POTENT;

D O I：

10.1080/14756366.2020.1740924

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

ATAD2 has been reported to play an important role in the processes of numerous cancers and validated to be a potential therapeutic target. This work is to discover potent ATAD2 inhibitors and elucidate the underlying mechanisms in breast cancer. A novel ATAD2 bromodomain inhibitor (AM879) was discovered by combining structure-based virtual screening with biochemical analyses. AM879 presents potent inhibitory activity towards ATAD2 bromodomain (IC50 = 3565 nM), presenting no inhibitory activity against BRD2-4. Moreover, AM879 inhibited MDA-MB-231 cells proliferation with IC50 value of 2.43 mu M, suppressed the expression of c-Myc, and induced significant apoptosis. Additionally, AM978 could induce autophagy via PI3K-AKT-mTOR signalling in MDA-MB-231 cells. This study demonstrates the development of potent ATAD2 inhibitors with novel scaffolds for breast cancer therapy.

引用

页码：713 / 725

页数：13

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