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

Dahong Yao; Jieshu You; Xuetao Yang; Jin Zhang; Xiaojun Yao

doi:10.1080/14756366.2023.2242601

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.

Authors

Dahong Yao^{1

2}, Jieshu You², Xuetao Yang², Jin Zhang³, Xiaojun Yao¹

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.

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.

MeSH terms

ATPases Associated with Diverse Cellular Activities / metabolism
Adenosine Triphosphatases / metabolism
Cell Proliferation
DNA-Binding Proteins / metabolism
Humans
Neoplasms*
Theophylline*

Substances

ATPases Associated with Diverse Cellular Activities
Theophylline
DNA-Binding Proteins
Adenosine Triphosphatases
ATAD2 protein, human

Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82003580, 82173666); Foundation Committee of basic and applied basic research of Guangdong Province (2019A1515110482), as well as Shenzhen science and technology research and development funds (Grant No. JCYJ20210324094612035, JCYJ20190808171803553, and 2022071718149001), Project supported by the High Level Talent Research Start-up Fund of Shenzhen Technology University (GDRC202123).