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Thomas, Sophie R. 
ORCID: https://orcid.org/0000-0003-1110-430X, Iellici, Thomas, Park, Mihyun, Klaus, Elisabeth, Bileck, Andrea, Gerner, Christopher, Meier-Menches, Samuel M. and Casini, Angela
(2026)
A Gold-PROTAC Degrades the Oncogenic Tyrosine Kinase MERTK: Insights into the Degradome from a Steady-State System.
ACS Chemical Biology, 21.
ISSN 1554-8929
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Abstract
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(AuPROTAC) 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 AuPROTAC was characterized by establishing a cycloheximide chase assay in a non proliferative steady-stateHL-60cell culture, enabling the identification of PROTAC degradation targets uncoupled from confounding effects originating from cell-cycle dependent translational patterns. The method was verified using the known SMARCA2 and PBRM1-degrader ACBI2. AuPROTAC could degrade the oncogenic tyrosine kinase MERTK and the thioredoxin-like 1 protein TXNL1. Their degradation was successfully rescued by proteasome inhibition. Proteome-wide degradation selectivity was further characterized by ranking the degraded targets according to the reduction extent of their protein half-lives. Interestingly, the AuPROTAC degraded a relatively limited number of proteins (95) when compared to ACBI2 (221).
| Item Type: | Article |
|---|---|
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 11 Sep 2026 14:30 |
| Last Modified: | 11 Sep 2026 14:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/104499 |
| DOI: | 10.1021/acschembio.5c00860 |
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