Design of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to Interrogate the Relationship of EGFR and GAK in Chordoma

We describe the design
of a set of inhibitors to investigate the
relationship between cyclin G associated kinase (GAK) and epidermal
growth factor receptor (EGFR) in chordoma bone cancers. These compounds
were characterized both in vitro and using in cell target engagement
assays. The most potent chordoma inhibitors were further characterized
in a kinome-wide screen demonstrating narrow spectrum profiles. While
we observed a direct correlation between EGFR and antiproliferative
effects on chordoma, GAK inhibition appeared to have only a limited
effect.