GSK215

GSK-215 is the most effective PROTAC for studying the in vivo degradation of FAK. GSK215 has been thoroughly characterised in biochemical and cellular assays. The crystal structure of the ternary complex formed underpins the high potency and the proteome-wide selectivity observed in A549 cells. Phenotypic assays demonstrate its effectiveness in inhibiting cell proliferation and motility. However, it should be noted that the results obtained at the cellular level are largely dependent on the cell type used. In vivo FAK degradation is observed at low doses in male CD1 mice, compared to other available PROTACs such as PROTAC-3 and BI-3663. This is a clear advantage if you are interested in further in vivo studies and potentially clinical trials.

GSK-215 represents a well validated degrader for FAK. GSK-215 exhibits high kinase selective for FAK (as determined by kinobead assay in lysate) and potent degradation in cells, DC50 = 1.3 nM, DMax ~99%. GSK-215 activity was validated by parent inhibitor competition and proteasome inhibitors, and has an FAK inactive enantiomeric control which is important for deconvoluting off-target effects, however whole proteome data with the inactive enantiomer could be included to give full confidence of off-target degradation. In vivo data in mice shows good and sustained degradation of FAK, even when GSK-215 concentration is below detectable levels.