TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1
Maria Kalyukina1,2, Yuliana Yosaatmadja1, Martin J Middleditch1
1School of Biological 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.
More Related Videos
Related Concept Videos
Factors Affecting Protein-Drug Binding: Drug-Related Factors
One crucial factor in drug-protein binding is the drug's lipophilicity or its affinity for fat. More lipophilic drugs tend to have higher binding extents. For example, highly lipophilic drugs like cloxacillin exhibit substantial protein binding, with as much as 95% of the drug binding to proteins. In...
Factors Affecting Protein-Drug Binding: Patient-Related Factors
Age stands as a key determinant in protein-drug binding. Neonates, characterized by low albumin content, experience heightened concentrations of unbound drugs such as phenytoin and...
Factors Affecting Protein-Drug Binding: Protein-Related Factors
The physicochemical properties of a drug play a significant role in its ability to bind to proteins. Lipophilic drugs, which dissolve in fats, oils, and lipids, can be...
Role of Hematopoietic Growth Factors
Thrombopoietin (TPO), mainly released by the liver,...
Factors Influencing Microbial Growth: pH
Internal Receptors


