Synthesis and identification of unprecedented selective inhibitors of CK1ε

Eur J Med Chem. 2015:96:308-17. doi: 10.1016/j.ejmech.2015.03.046. Epub 2015 Apr 14.

Abstract

A small and structure-biased library of enantiopure anti-β-amino alcohols was prepared in a straightforward manner by a simplified version of the Reetz protocol. Antiproliferative activity testing against a panel of five human solid tumor cell lines gave GI50 values in the range 1-20 μM. The reverse screening by computational methods against 58 proteins involved in cancer pointed to kinases as possible therapeutic target candidates. The experimental determination of the interaction with 456 kinases indicated that the compounds behave as selective CK1ε inhibitors. Our results demonstrate that the lead compound represents the first selective CK1ε inhibitor with proven antiproliferative activity in cancer cell lines.

Keywords: Antitumor agents; Casein kinase 1 epsilon; Enzyme inhibitors; Sphingoid bases; Target fishing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Alcohols / chemical synthesis
  • Amino Alcohols / chemistry
  • Amino Alcohols / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Casein Kinase 1 epsilon / antagonists & inhibitors*
  • Casein Kinase 1 epsilon / metabolism
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Amino Alcohols
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Casein Kinase 1 epsilon