Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold

Bioorg Med Chem Lett. 2015 Jan 15;25(2):367-71. doi: 10.1016/j.bmcl.2014.11.030. Epub 2014 Nov 20.


A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.

Keywords: BTK; Bruton’s Tyrosine Kinase; Fluorine scan; Rational fluorine scan; Structure-based drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Crystallography, X-Ray
  • Fluorine / chemistry*
  • Fluorine / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / chemistry*
  • Protein-Tyrosine Kinases / metabolism*
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • Fluorine
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human