Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton's tyrosine kinase inhibitors

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3052-3059. doi: 10.1016/j.bmcl.2016.05.014. Epub 2016 May 7.

Abstract

A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07μM. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.

Keywords: BTK; Covalent kinase inhibitor; Molecular dynamics simulation; Pyrimidine; Structure–activity relationship.

MeSH terms

  • Adenine / analogs & derivatives
  • Agammaglobulinaemia Tyrosine Kinase
  • Catalytic Domain
  • Hydrogen Bonding
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Piperidines
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry
  • Pyrazoles / chemistry
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • Adenine