Fragment-based Design, Synthesis and Biological Evaluation of Theophylline Derivatives As ATAD2 Inhibitors in BT-549 Cells

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2023 Aug 3

PMID 37533352

Authors

Dahong Yao

Jieshu You

Xuetao Yang

Jin Zhang

Xiaojun Yao

Affiliations

Soon will be listed here.

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 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.

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