6MZQ

TAS-120 in reversible binding mode with FGFR1

Summary for 6MZQ

• Entry DOI: 10.2210/pdb6mzq/pdb
• Descriptor: Fibroblast growth factor receptor 1, 1-[(3S)-3-{4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}pyrrolidin-1-yl]prop-2-en-1-one (3 entities in total)
• Functional Keywords: fgfr1, tas-120, inhibitor, complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 71544.12

Authors

Kalyukina, M.,Squire, C.J. (deposition date: 2018-11-05, release date: 2019-01-16, Last modification date: 2023-10-11)

Primary citation

Kalyukina, M.,Yosaatmadja, Y.,Middleditch, M.J.,Patterson, A.V.,Smaill, J.B.,Squire, C.J.
TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure.
ChemMedChem, 14:494-500, 2019

PubMed 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.

PubMed: 30600916
DOI: 10.1002/cmdc.201800719

Experimental method

X-RAY DIFFRACTION (2 Å)