Abstract
Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.
Highlights
Fibroblast growth factor receptors (FGFRs) are transmembrane receptor tyrosine kinases that transmit cellular signaling by binding FGFs
We posited that this phenomenon was due to an increase in the dihedral angle between the 6-position phenyl and indazole ring, which in turn would be better tolerated within FGFR1 over FGFR2
X-ray crystallographic studies outlined that ligand electron density surrounding the 6position phenyl ring was more spherical in FGFR1 over FGFR2
Summary
FGFRs are transmembrane receptor tyrosine kinases that transmit cellular signaling by binding FGFs. Type I and I1/2 inhibitors occupy the ATP-binding site with the Asp-Phe-Gly (DFG) motif, a conserved region of the activation loop, exhibiting an “in” conformation (Figure S1A), with Type I and I1/2 inhibitors targeting the active and inactive forms of the kinase, respectively. Type II inhibitors bind within the ATP binding pocket with a “DFG-out” conformation (Figure S1B) and solely bind the inactive form of the kinase. These inhibitors offer an advantage over Type I inhibitors in that their binding modes are noncompetitive with ATP and may overcome issues of selectivity arising from the structural similarities of kinase ATP binding pockets.. These inhibitors offer an advantage over Type I inhibitors in that their binding modes are noncompetitive with ATP and may overcome issues of selectivity arising from the structural similarities of kinase ATP binding pockets. Ponatinib is a Type II inhibitor and gained accelerated FDA approval for the rare disease chronic myeloid leukemia in 2012, where
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