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

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.
Maria Kalyukina 1 2 Yuliana Yosaatmadja 1 Martin J Middleditch 1 Adam V Patterson 3 2 Jeff B Smaill 3 2 Christopher J Squire 1 2
Affiliations

Affiliations

  • 1 School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
  • 2 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
  • 3 Auckland Cancer Society Research Centre, Faculty of Medicine and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Abstract

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.

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