Structures of the Tyrosine Kinase Domain of Fibroblast Growth Factor Receptor in Complex with Inhibitors

TLDR

A new class of protein tyrosine kinase inhibitors based on an oxindole core (indolinones) has been identified. The structural data aim to aid the design of novel inhibitors for treating cancers and other diseases driven by tyrosine‑kinase signaling. Crystal structures of the FGFR1 kinase domain with the two oxindole inhibitors were solved, showing the oxindole core occupying the ATP adenine pocket and its extensions contacting hinge residues between the lobes. The two inhibitors potently blocked FGFR1 activity with differing specificity for other RTKs, and the more selective compound induced a conformational change in the nucleotide‑binding loop.

Abstract

A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.