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 Hbond which could be utilized to design more selective FGFR2 inhibitors.

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 for FGFRimplicated malignancies. Pan-FGFR inhibitors often cause toxic side-effects via off-target inhibition and very few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach towards the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series that exhibited moderate sub-micromolar activity against FGFRs 1-3. Subsequent synthesis, biological evaluation, and iterative rounds of SBDD led to an inhibitor with nM 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. Subsequent X-ray crystallographic studies revealed significant morphological differences in the P-loop flanking the ATP-binding pocket which appeared to be determined by which inhibitor was bound. It was posited that this dynamic phenomenon was fundamental to the selectivity of these compounds and complementary to current theories surrounding sub-type FGFR2 selectivity. In addition, several derivatives exhibited low µM potency against FGFR1/2-activated cell lines and underlined the potential of these compounds for development into medicines for the treatment of FGFR-driven cancers.

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 for FGFR-implicated malignancies. Pan-FGFR inhibitors often cause toxic side-effects via off-target inhibition and very few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach towards the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series that exhibited moderate sub-micromolar activity against FGFRs 1–3. Subsequent synthesis, biological evaluation, and iterative rounds of SBDD led to an inhibitor with nM 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. Subsequent X-ray crystallographic studies revealed significant morphological differences in the P-loop flanking the ATP-binding pocket which appeared to be determined by which inhibitor was bound. It was posited that this dynamic phenomenon was fundamental to the selectivity of these compounds and complementary to current theories surrounding sub-type FGFR2 selectivity. In addition, several derivatives exhibited low µM potency against FGFR1/2-activated cell lines and underlined the potential of these compounds for development into medicines for the treatment of FGFR-driven cancers.