PROTAC FAK degrader 1

It is also worth considering the use of GSK215, as this FAK-targeted PROTAC has been found to exhibit potent FAK degradation activity even in mice following a subcutaneous injection. See: Law RP, Nunes J, Chung CW, et al. Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs. Angew Chem Int Ed Engl. 2021;60(43):23327-23334. doi:10.1002/anie.202109237.

First FAK degrader with very good in-vitro potency and rate of degradation with a Dmax >99%. The compound potently inhibited FAK downstream signaling, such as Axilin and Akt phosphorylation, and was effective in wound healing and Transwell cell-invasion assays using MDA-MB-231 cells. However, proteasome-dependent inhibition in the presence of a proteasome inhibitor was not tested. As PROTAC-3 is derived from the multikinase inhibitor Defactinib, the selectivity of the compound might be a limiting factor. Although showing a slightly better selectivity profile than the lead, the off-target activity was not completely analysed in a cellular context. A corresponding negative control, PROTAC-7, is available and shows equally potent inhibition of FAK but does not degrade the protein (IC50 = 11 nM, Dmax = 0%). In summary, I would still recommend the compound, as there are currently no better alternatives available. Better profiling in terms of selectivity would be desirable and results should therefore be interpreted with caution.