SGK3 is a protein kinase containing a PX domain, activated at endosomes downstream of class 1 and 3 PI3K family members through growth factors and oncogenic mutations. It plays a pivotal role in conferring resistance to breast cancer cells against class 1 PI3K or Akt inhibitors, effectively compensating for the loss of Akt activity and reinstating proliferative pathways like mTORC1 signaling. Hence, it is imperative to develop potent tools for targeting SGK3 and disrupting its contribution to inhibitor resistance. In this context, we detail the creation of SGK3-PROTAC1, a PROTAC conjugate comprising the 308-R SGK inhibitor and the VH032 VHL binding ligand, designed to induce degradation of SGK3. SGK3-PROTAC1 (0.3 μM) achieved 50% degradation of endogenous SGK3 within 2 hours, with a maximum of 80% degradation observed within 8 hours. This degradation was accompanied by the loss of phosphorylation of NDRG1, an SGK3 substrate. Notably, SGK3-PROTAC1 did not induce degradation of closely related SGK1 and SGK2 isoforms, which are nonetheless engaged and inhibited by 308-R.
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