Figure 1.

Schematic of PROTAC design and activity. (A) Schematic of StIP binding to PKA along with parent sequence. * = (S)-2-(4-pentenyl)alanine. (B) Schematic of PROTAC structure. StIP-derived peptide is conjugated to thalidomide-derived Cereblon Ligand 1 via a PEG-8 linker. (C) Proposed mechanism of action of PKI-derived PROTAC molecule. StIP-derived POI ligand binds PKA and recruits E3 ligase complex via Cereblon Ligand 1, resulting in ubiquitination (Ub) of PKA and subsequent targeted degradation by the proteasome. E2 = E2 ligase, E3 = E3 ligase.