Discovery of DCAF16-based PROTACs as SHP2 degraders.

The overexpression of SHP2 in various cancers establishes it as an attractive therapeutic target. Growing evidence indicates that the scaffold function of SHP2 contributes significantly to its oncogenic signaling and tumorigenesis. Unlike traditional inhibitors, PROTACs can simultaneously eliminate both the enzymatic and scaffold functions of the target protein, representing a more promising therapeutic strategy. Herein, we report the design and synthesis of SHP2 PROTACs that recruit the DCAF16 E3 ligase for targeted SHP2 degradation. Among which, SK8 exhibited the most potent anti-tumor activity. SK8 induced SHP2 degradation in a concentration- and time-dependent manner via the ubiquitin-proteasome system. Notably, under the tested experimental conditions, SK8 produced greater inhibition of cell proliferation, migration, and invasion, together with increased apoptosis, compared with SHP099. Preliminary mechanistic studies revealed that this enhanced potency stemmed from a more profound inhibition of RAS/MAPK and PI3K/AKT/mTOR signaling, coupled with the reversal of IFN-γ/JAK/STAT1 suppression. Overall, our findings support the potential of SHP2-targeted protein degradation as an alternative strategy to enzymatic inhibition and provide a promising starting point for the further development of SHP2 degraders.