Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry

Bioorg Med Chem. 2021 Jul 15;42:116223. doi: 10.1016/j.bmc.2021.116223. Epub 2021 May 19.


Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority of reported projects describe the discovery of reversible, i.e. non-covalent, target modulators. We synthesized multiple DNA-encoded chemical libraries terminated in electrophiles and then used them to discover covalent irreversible inhibitors and report the successful discovery of acrylamide- and epoxide-terminated Bruton's Tyrosine Kinase (BTK) inhibitors. We also demonstrate their selectivity, potency and covalent cysteine engagement using a range of techniques including X-ray crystallography, thermal transition shift assay, reporter displacement assay and intact protein complex mass spectrometry. The epoxide BTK inhibitors described here are the first ever reported to utilize this electrophile for this target.

Keywords: Bruton’s Tyrosine Kinase; Covalent Irreversible Inhibitor; DNA-Encoded Chemical Libraries (DECL); Drug Discovery; Epoxide; Tryptoline.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Crystallography, X-Ray
  • DNA / chemistry*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • DNA
  • Agammaglobulinaemia Tyrosine Kinase