Kalyukina, M., et al. TAS‐120 cancer target binding; defining reactivity and revealing the first FGFR1 irreversible structure. ChemMedChem. 2/1/2019.
TAS-120 is an irreversible inhibitor of the fibroblast growth factor receptor (FGFR) family that 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.