A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066

Bioorg Med Chem. 2017 Jul 1;25(13):3471-3482. doi: 10.1016/j.bmc.2017.04.037. Epub 2017 Apr 30.

Abstract

Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.

Keywords: CK2; Fragment linking; Fragment-based drug discovery; Kinase inhibition; Molecular modelling.

MeSH terms

  • Binding Sites / drug effects
  • Biphenyl Compounds / chemical synthesis
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Biphenyl Compounds
  • CAM4066
  • Protein Kinase Inhibitors
  • CSNK2A1 protein, human
  • Casein Kinase II