Optimization and biological evaluation of 2-aminobenzothiazole derivatives as Aurora B kinase inhibitors

Bioorg Med Chem. 2017 Jul 15;25(14):3614-3622. doi: 10.1016/j.bmc.2017.04.004. Epub 2017 Apr 6.

Abstract

A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G2/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics.

Keywords: Aminobenzothiazole; Antiproliferation; Aurora B kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / metabolism
  • Aurora Kinase B / antagonists & inhibitors*
  • Aurora Kinase B / metabolism
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / chemistry*
  • Benzothiazoles / pharmacology
  • Benzothiazoles / toxicity
  • Binding Sites
  • Catalytic Domain
  • Cell Proliferation / drug effects
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • Molecular Docking Simulation
  • Morpholines / chemical synthesis
  • Morpholines / chemistry*
  • Morpholines / toxicity
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • (4-bromophenyl)-3-(4-((6-(2-morpholin-4-ylethoxy)benzothiazol-2-ylamino)methyl)phenyl)urea
  • Antineoplastic Agents
  • Benzothiazoles
  • Histones
  • Morpholines
  • Protein Kinase Inhibitors
  • aminobenzothiazole compound
  • Aurora Kinase A
  • Aurora Kinase B