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

Tytuł:: Discovery of novel ATAD2 bromodomain inhibitors that trigger apoptosis and autophagy in breast cells by structure-based virtual screening.
Autorzy:: Yao D; Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China.; Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural small molecule Drugs, Engineering Laboratory of Shenzhen Natural small molecule Innovative Drugs, Shenzhen University Health Science Center, Shenzhen, China.
Zhang J; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China.
Wang J; Shenzhen Honghui Bio-Pharmaceutical Co. Ltd., Shenzhen, China.
Pan D; Institute of Traditional Chinese Medicine & Natural Products, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, P. R. China.
He Z; Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China.; Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural small molecule Drugs, Engineering Laboratory of Shenzhen Natural small molecule Innovative Drugs, Shenzhen University Health Science Center, Shenzhen, China.
Źródło:: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2020 Dec; Vol. 35 (1), pp. 713-725.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
MeSH Terms:: Drug Discovery*
ATPases Associated with Diverse Cellular Activities/*antagonists & inhibitors
Antineoplastic Agents/*pharmacology
Apoptosis/*drug effects
Breast Neoplasms/*drug therapy
DNA-Binding Proteins/*antagonists & inhibitors
ATPases Associated with Diverse Cellular Activities/metabolism ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Proliferation/drug effects ; DNA-Binding Proteins/metabolism ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drug Screening Assays, Antitumor ; Humans ; Models, Molecular ; Molecular Structure ; Structure-Activity Relationship ; Tumor Cells, Cultured
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Contributed Indexing:: Keywords: ATAD2; Virtual Screening; apoptosis; autophagy; breast cancer
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (DNA-Binding Proteins)
EC 3.6.1.3 (ATAD2 protein, human)
EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities)
Entry Date(s):: Date Created: 20200317 Date Completed: 20201027 Latest Revision: 20201027
Update Code:: 20240105
PubMed Central ID:: PMC7144325
DOI:: 10.1080/14756366.2020.1740924
PMID:: 32174193
: Czasopismo naukowe

Pełny tekst

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 (IC 50 = 3565 nM), presenting no inhibitory activity against BRD2-4. Moreover, AM879 inhibited MDA-MB-231 cells proliferation with IC 50 value of 2.43 µM, 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.

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