Discovery of Tricyclic Pyranochromenone as Novel Bruton's Tyrosine Kinase Inhibitors with in Vivo Antirheumatic Activity

Int J Mol Sci. 2020 Oct 25;21(21):7919. doi: 10.3390/ijms21217919.


Bruton's tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a novel scaffold that occupies the adenine-binding site of BTK. We screened an in-house library of natural products and their analogs via a biochemical assay to identify a novel scaffold for targeting BTK. A pyranochromenone scaffold, derived from a natural active component decursin, was found to be effective at targeting BTK and was selected for further optimization. A series of pyranochromenone analogs was synthesized through the modification of pyranochromenone at the C7 position. Pyranochromenone compounds with an electrophilic warhead exhibited promising BTK inhibitory activity, with IC50 values in the range of 0.5-0.9 µM. A docking study of the representative compound 8 provided a reasonable explanation for compound activity. Compound 8 demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound 8 presented significant in vivo efficacy in a murine model of collagen-induced arthritis.

Keywords: BTK inhibitor; irreversible inhibitor; pyranochromenone; rheumatoid arthritis.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / chemistry
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Animals
  • Antirheumatic Agents / chemistry
  • Antirheumatic Agents / pharmacology*
  • Arthritis, Experimental / prevention & control
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Butyrates / chemistry
  • Butyrates / pharmacology*
  • Humans
  • Male
  • Mice, Inbred DBA
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Domains
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • THP-1 Cells


  • Antirheumatic Agents
  • Benzopyrans
  • Biological Products
  • Butyrates
  • Protein Kinase Inhibitors
  • decursin
  • Agammaglobulinaemia Tyrosine Kinase