Optimization and biological evaluation of nicotinamide derivatives as Aurora kinase inhibitors

Bioorg Med Chem. 2019 Sep 1;27(17):3825-3835. doi: 10.1016/j.bmc.2019.07.016. Epub 2019 Jul 11.

Abstract

Aurora kinases are known to be overexpressed in various solid tumors and implicated in oncogenesis and tumor progression. A series of nicotinamide derivatives were synthesized and their biological activities were evaluated, including kinase inhibitory activity against Aur A and Aur B and in vitro antitumor activity against SW620, HT-29, NCI-H1975 and Hela cancer cell lines. In addition, the study of antiproliferation, cytotoxicity and apoptosis was performed meanwhile. As the most potent inhibitor of Aur A, 4-((3-bromo-4-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)nicotinamide (10l) showed excellent antitumor activity against SW620 and NCI-H1975 with IC50 values were 0.61 and 1.06 μM, while the IC50 values of reference compound were 3.37 and 6.67 μM, respectively. Furthermore, binding mode studies indicated that compound 10l forms better interaction with Aur A.

Keywords: Antitumor; Aurora kinases; Kinase inhibitors; Nicotinamide; SAR.

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
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HT29 Cells
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Niacinamide / chemical synthesis
  • Niacinamide / chemistry
  • Niacinamide / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Niacinamide
  • AURKA protein, human
  • AURKB protein, human
  • Aurora Kinase A
  • Aurora Kinase B