Structure-based design and synthesis of imidazo[1,2-a]pyridine derivatives as novel and potent Nek2 inhibitors with in vitro and in vivo antitumor activities

Eur J Med Chem. 2017 Jan 27;126:1083-1106. doi: 10.1016/j.ejmech.2016.12.026. Epub 2016 Dec 12.


We present herein the discovery and development of novel and potent Nek2 inhibitors with distinctive in vitro and in vivo antitumor activity based on an imidazo[1,2-a]pyridine scaffold. Our studies identified a nonlinear SAR for activity against both Nek2 and cancer cells. Bioisostere and structure-based design techniques were employed to identify compounds 42c (MBM-17, IC50 = 3.0 nM) and 42g (MBM-55, IC50 = 1.0 nM), which displayed low nanomolar activity and excellent selectivity for Nek2. Both compounds effectively inhibited the proliferation of cancer cells by inducing cell cycle arrest and apoptosis. Importantly, the salts form of these two compounds (MBM-17S and MBM-55S) significantly suppressed tumor growth in vivo without apparent toxicity based on appearance and changes in body weight. In summary, MBM-17 and MBM-55 displayed the potential for substantial therapeutic application in cancer treatment.

Keywords: Antitumor activity; Imidazo[1,2-a]pyridine; Nek2 inhibitors; Selectivity.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • Male
  • Mice
  • Molecular Docking Simulation
  • NIMA-Related Kinases / antagonists & inhibitors*
  • NIMA-Related Kinases / chemistry
  • NIMA-Related Kinases / metabolism
  • Nitrazepam / chemistry*
  • Polyploidy
  • Protein Conformation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • Nitrazepam
  • NEK2 protein, human
  • NIMA-Related Kinases