2. Academic Validation
  3. Fragment-based design, synthesis and biological evaluation of theophylline derivatives as ATAD2 inhibitors in BT-549 cells

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

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):2242601. doi: 10.1080/14756366.2023.2242601.
Dahong Yao 1 2,  Jieshu You 2,  Xuetao Yang 2,  Jin Zhang 3,  Xiaojun Yao 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.
  • 2 School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, China.
  • 3 School of Pharmaceutical Sciences, Medical School, Shenzhen University, Shenzhen, China.
PMID: 37533352 DOI: 10.1080/14756366.2023.2242601
Abstract

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 19f) is discovered with an IC50 value of 0.27 μM against ATAD2, which adopts a combination of classic and atypical binding mode. Additionally, compound 19f 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.

Keywords

ATAD2; TNBC; apoptosis; fragment-based; migration.

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