Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders

Eur J Med Chem. 2017 Dec 1:141:657-675. doi: 10.1016/j.ejmech.2017.10.003. Epub 2017 Oct 4.

Abstract

Tyrosine kinases including LCK and FMS are involved in inflammatory disorders as well as many types of cancer. Our team has designed and synthesized thirty novel pyrimidine based inhibitors targeting LCK, classified into four different series (amides, ureas, imines (Schiff base) and benzylamines). Twelve of them showed nanomolar IC50 values. Compound 7g showed excellent selectivity profile and was selectively potent over FMS kinase (IC50 value of 4.6 nM). Molecular docking study was performed to help us rationalize the obtained results and predict the possible binding mode for our compounds in both LCK and FMS. Based on the obtained biological assay data and modelling results, a detailed SAR study was discussed. As a further testing regarding the anti-inflammatory effect of the new compounds, in vitro cellular assay over RAW 264.7 macrophages was performed. Compound 7g exhibited excellent anti-inflammatory effect. Therefore, we report the design of novel phenoxypyrimidine derivatives as potent and selective LCK inhibitors and the discovery of 7g as potent and selective FMS/LCK dual inhibitor for the potential application in inflammatory disorders including rheumatoid arthritis (RA).

Keywords: FMS; Inflammation; LCK; Molecular docking and RAW 264.7 macrophages; Synthesis.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • RAW 264.7 Cells
  • Receptors, Colony-Stimulating Factor / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Receptors, Colony-Stimulating Factor
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)