jm1c01163_si_002.csv (4.33 kB)
From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor
datasetposted on 2021-11-16, 01:04 authored by Lewis D. Turner, Chi H. Trinh, Ryan A. Hubball, Kyle M. Orritt, Chi-Chuan Lin, Julie E. Burns, Margaret A. Knowles, Colin W. G. Fishwick
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.
subsequent iterative roundsspecific morphological differencesfgfr inhibitors currentlybiological evaluation ledadditional docking studiesguided approach towardselective inhibitors existexisting fragment seriesexhibited moderate selectivityde novo designselective fgfr2 inhibitorslead inhibitor resultedselective fgfr2 inhibitoryield compounds predictedselective hsubtle changesnanomolar potencyimprove potencydevelopment towardcomplete lossclinical trials