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

• Published in: ChemMedChem Vol. 14; no. 4; pp. 494 - 500
• Main Authors: Kalyukina, Maria, Yosaatmadja, Yuliana, Middleditch, Martin J., Patterson, Adam V., Smaill, Jeff B., Squire, Christopher J.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 19.02.2019
• Subjects: Acrylamide; Cancer; Chemical reactions; Clinical trials; conformational sampling; Coordination compounds; Covalence; Crystal structure; drug discovery; Fast chemical reactions; fibroblast growth factor receptor; Fibroblast growth factor receptor 1; Fibroblast growth factor receptors; Fibroblasts; Growth factors; Inhibitors; irreversible inhibitor; Kinases; Mass spectrometry; Mass spectroscopy; Medical research; Metastases; Organic chemistry; Protein-tyrosine kinase; Proteins; Reactivity; Solid tumors; TAS-120; Tumors; Tyrosine; irreversible inhibitor; conformational sampling; drug discovery; TAS-120; fibroblast growth factor receptor
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800719

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. Revealing snapshots: The extreme reactivity of TAS‐120 toward cancer target fibroblast growth factor receptor kinases was revealed by mass spectrometry and by a sequence of three X‐ray crystallography “snapshots” of the inhibitory process. Free ligand, reversible, and irreversible structures show each step of the covalent modification of the target. We propose that TAS‐120 samples a multitude of conformations of the highly flexible P‐loop in the target kinases.