biostudies-literatureUnknown21(1)Thomas SRProteolysis targeting chimeras (PROTACs) are bifunctional molecules designed to induce the degradation of specific proteins within a cell. While most PROTACs are noncovalent interactors, covalent PROTACs may benefit from improved selectivity and pharmacodynamics, yet remain largely understudied. Here, a covalent gold-based PROTAC (<b>AuPROTAC</b>) was synthesized, featuring a Au(III)-warhead, known to induce cysteine-arylation in a gold-templated two-step mechanism, linked to a cereblon binding moiety. The degradome of the <b>AuPROTAC</b> was characterized by establishing a cycloheximide chase assay in a nonproliferative steady-state HL-60 cell culture, enabling the identification of PROTAC degradation targets uncoupled from confounding effects originating from cell-cycle-dependent translaACS chemical biology170-186https://www.ebi.ac.uk/biostudies/studies/S-EPMC12813982biostudies-literatureA Gold-PROTAC Degrades the Oncogenic Tyrosine Kinase MERTK: Insights into the Degradome from a Steady-State System.PMC12813982Casini AGerner CThomas SRMeier-Menches SMPark MIellici TBileck AKlaus EfalseA Gold-PROTAC Degrades the Oncogenic Tyrosine Kinase MERTK: Insights into the Degradome from a Steady-State System.Proteolysis targeting chimeras (PROTACs) are bifunctional molecules designed to induce the degradation of specific proteins within a cell. While most PROTACs are noncovalent interactors, covalent PROTACs may benefit from improved selectivity and pharmacodynamics, yet remain largely understudied. Here, a covalent gold-based PROTAC (<b>AuPROTAC</b>) was synthesized, featuring a Au(III)-warhead, known to induce cysteine-arylation in a gold-templated two-step mechanism, linked to a cereblon binding moiety. The degradome of the <b>AuPROTAC</b> was characterized by establishing a cycloheximide chase assay in a nonproliferative steady-state HL-60 cell culture, enabling the identification of PROTAC degradation targets uncoupled from confounding effects originating from cell-cycle-dependent transla2026-01-01T00:00:00Z2026 Jan2026-07-15T13:31:34.842Z2026-07-05T03:08:34.868ZS-EPMC128139824148655710.1021/acschembio.5c00860