Fragment-based design, synthesis and biological evaluation of theophylline derivatives as ATAD2 inhibitors in BT-549 cells

ATPase family AAA domain-containing protein 2 (ATAD2) has been emerging as a hot anti-cancer drugable target due to its oncogenic epigenetic modification closely associated with cancer cells proliferation, apoptosis, migration and drug resistance. In this study, we design a series of theophylline de...

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Published in:Journal of enzyme inhibition and medicinal chemistry 2023-12, Vol.38 (1), p.2242601-2242601
Main Authors: Yao, Dahong, You, Jieshu, Yang, Xuetao, Zhang, Jin, Yao, Xiaojun
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - metabolism
Apoptosis
ATAD2
ATPases Associated with Diverse Cellular Activities - metabolism
Breast cancer
c-Myc protein
Cancer therapies
Cell cycle
Cell growth
Cell migration
Cell Proliferation
Design
DNA-Binding Proteins - metabolism
Drug development
Drug resistance
Epigenetics
fragment-based
Humans
Hydrocarbons
Hydrogen bonds
migration
Myc protein
Neoplasms
Pharmaceutical sciences
Theophylline
TNBC
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Summary:ATPase family AAA domain-containing protein 2 (ATAD2) has been emerging as a hot anti-cancer drugable target due to its oncogenic epigenetic modification closely associated with cancer cells proliferation, apoptosis, migration and drug resistance. In this study, we design a series of theophylline derivatives as novel ATAD2 inhibitors through fragment-based screening and scaffold growth strategy. A novel potent ATAD2 inhibitor (compound is discovered with an IC value of 0.27 μM against ATAD2, which adopts a combination of classic and atypical binding mode. Additionally, compound could impede ATAD2 activity and c-Myc activation, induced significant apoptosis, and illustrated an anti-migration effect in BT-549 cells. Collectively, these results provide new enlightenment for the development of novel potent ATAD2 inhibitors for triple-negative breast cancer (TNBC) treatment.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2023.2242601