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

J Enzyme Inhib Med Chem. 2020 Dec;35(1):713-725. doi: 10.1080/14756366.2020.1740924.

Abstract

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 (IC50 = 3565 nM), presenting no inhibitory activity against BRD2-4. Moreover, AM879 inhibited MDA-MB-231 cells proliferation with IC50 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.

Keywords: ATAD2; Virtual Screening; apoptosis; autophagy; breast cancer.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / antagonists & inhibitors*
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • ATAD2 protein, human
  • ATPases Associated with Diverse Cellular Activities