TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure

ChemMedChem. 2019 Feb 19;14(4):494-500. doi: 10.1002/cmdc.201800719. Epub 2019 Jan 14.


1-[(3S)-3-[4-Amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one (TAS-120) is an irreversible inhibitor of the fibroblast growth factor receptor (FGFR) family, and is currently under phase I/II clinical trials in patients with confirmed advanced metastatic solid tumours harbouring FGFR aberrations. This inhibitor specifically targets the P-loop of the FGFR tyrosine kinase domain, forming a covalent adduct with a cysteine side chain of the protein. Our mass spectrometry experiments characterise an exceptionally fast chemical reaction in forming the covalent complex. The structural basis of this reactivity is revealed by a sequence of three X-ray crystal structures: a free ligand structure, a reversible FGFR1 structure, and the first reported irreversible FGFR1 adduct structure. We hypothesise that the most significant reactivity feature of TAS-120 is its inherent ability to undertake conformational sampling of the FGFR P-loop. In designing novel covalent FGFR inhibitors, such a phenomenon presents an attractive strategy requiring appropriate positioning of an acrylamide group similarly to that of TAS-120.

Keywords: TAS-120; conformational sampling; drug discovery; fibroblast growth factor receptor; irreversible inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Humans
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry


  • Pyrazoles
  • Pyrimidines
  • Recombinant Proteins
  • pyrazolo(3,4-d)pyrimidine
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1