Discovery of a novel small-molecule inhibitor of Fam20C that induces apoptosis and inhibits migration in triple negative breast cancer

Eur J Med Chem. 2021 Jan 15:210:113088. doi: 10.1016/j.ejmech.2020.113088. Epub 2020 Dec 7.

Abstract

The family with sequence similarity 20, member C (Fam20C), a Golgi casein kinase, has been recently regarded as a potential therapeutic target for the treatment of triple negative breast cancer (TNBC). Lacking enzyme activity center has been becoming an obstacle to the development of small-molecule inhibitors of Fam20C. Herein, we combined in silico high-throughput screening with chemical synthesis methods to obtain a new small-molecule Fam20C inhibitor 3r, which exhibited desired anti-proliferative activities against MDA-MB-231 cells and also inhibited migration. Subsequently, the enzymatic assay, molecular docking, and molecular dynamics (MD) simulations were carried out for validating that 3r could bind to Fam20C. In addition, 3r was found to induce apoptosis via the mitochondrial pathway in MDA-MB-231 cells as well as to inhibit cell migration. Moreover, we demonstrated that 3r inhibited tumor growth in vivo and thereby having a good therapeutic potential on TNBC. Taken together, these results suggest that 3r may be a novel Fam20C inhibitor with anti-proliferative and apoptosis-inducing activities, which would shed light on discovering more small-molecule drugs for the future TNBC therapy.

Keywords: Apoptosis; Fam20C; Migration; Small-molecule inhibitor; Triple negative breast cancer (TNBC).

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Casein Kinase I / antagonists & inhibitors*
  • Casein Kinase I / metabolism
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Extracellular Matrix Proteins / antagonists & inhibitors*
  • Extracellular Matrix Proteins / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Antineoplastic Agents
  • Extracellular Matrix Proteins
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Casein Kinase I
  • FAM20C protein, human