A Gold-PROTAC Degrades the Oncogenic Tyrosine Kinase MERTK: Insights into the Degradome from a Steady-State System
- Author(s)
- Sophie R Thomas, Thomas Iellici, Mihyun Park, Elisabeth Klaus, Andrea Bileck, Christopher Gerner, Samuel M Meier-Menches, Angela Casini
- 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 nonproliferative steady-state HL-60 cell 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).
- Organisation(s)
- Department of Inorganic Chemistry, Department of Analytical Chemistry, Joint Metabolome Facility
- External organisation(s)
- Technische Universität München, Vienna Doctoral School in Chemistry (DoSChem)
- Journal
- ACS Chemical Biology
- Volume
- 21
- Pages
- 170-186
- No. of pages
- 17
- ISSN
- 1554-8929
- DOI
- https://doi.org/10.1021/acschembio.5c00860
- Publication date
- 01-2026
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104004 Chemical biology, 106037 Proteomics, 104002 Analytical chemistry
- Keywords
- ASJC Scopus subject areas
- Biochemistry, Molecular Medicine
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/af6c54e7-97d6-467f-aaac-1a8856104bc8