Identification of actionable targeted protein degradation effector sites through Site-specific Ligand Incorporation-induced Proximity (SLIP).

ABSTRACT: Targeted protein degradation (TPD) is a rapidly emerging and potentially transformative therapeutic modality. However, the large majority of >600 known ubiquitin ligases have yet to be exploited as TPD effectors by proteolysis-targeting chimeras (PROTACs) or molecular glue degraders (MGDs). We report here a chemical-genetic platform, Site-specific Ligand Incorporation-induced Proximity (SLIP), to identify actionable ("PROTACable") sites on any potential effector protein in intact cells. SLIP uses genetic code expansion (GCE) to encode copper-free "click" ligation at a specific effector site in intact cells, enabling in situ formation of a covalent PROTAC-effector conjugate against a target protein of interest (POI). Modification at actionable effector sites drives degradation of the

SUBMITTER: Xiao Z 

PROVIDER: S-EPMC11838594 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature