Oligo-PROTAC strategy for cell-selective and targeted degradation of activated STAT3.

ABSTRACT: Decoy oligodeoxynucleotides (ODNs) allow targeting undruggable transcription factors, such as STAT3, but their limited potency and lack of delivery methods hampered translation. To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3D^PROTAC). STAT3D^PROTAC downregulated STAT3 in target cells, but not STAT1 or STAT5. Computational modeling of the STAT3D^PROTAC ternary complex predicted two surface lysines, K601 and K626, in STAT3 as potential ubiquitination sites. Accordingly, K601/K626 point mutations in STAT3, as well as proteasome inhibition or cereblon deletion, alleviated STAT3D^PROTAC effect. Next, we conjugated STA

SUBMITTER: Hall J 

PROVIDER: S-EPMC10879796 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature