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Discovery of ferroptosis-inducing R4VP compounds for targeting aggressive cancers.
Oncogene 45, 2727-2742 (2026)
Aggressive and therapy-resistant cancers present a significant challenge to treatment and are associated with poor patients’ survival. Identifying molecular pathways and compounds that target these pathways is critical for improving patient outcomes. RNF4, an E3 Ubiquitin ligase, is pivotal for tumorigenesis in part by stabilizing oncoproteins and its role in DNA repair, thereby enhancing cancer cell survival and driving tumorigenesis. Elevated RNF4 levels are associated with poor prognosis in patients with carcinomas, melanoma, and sarcoma. Here, we describe the design and development of R4VPs, dual degrader compounds connecting two E3 ubiquitin ligases; Von Hippel-Lindau protein (VHL) with RNF4. R4VPs promote RNF4 degradation and thereby reduce the levels of its stabilized phosphorylated oncoproteins, while concomitantly eliminating VHL. R4VPs selectively induce ferroptotic cell death in cancer cells, sparing non-tumorigenic and primary cells in part by binding and modifying the anti-ferroptotic selanoproteins GPX4. R4VPs-induced ferroptosis preferentially targeting cells harboring tumor-driving mutations in the EGFR pathway, whereas it does not affect PI3K-transformed cells. As a consequence, R4VPs effectively induce cell death in Receptor Tyrosine Kinase inhibitor-resistant melanoma and primary patient sarcoma cells. Our findings highlight the potential of selective ferroptosis inducers, such as R4VPs, as a therapeutic strategy for hard-to-treat cancers.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Protein-degradation; Ubiquitin Ligases; Cell-death; Sumo; Rnf4; Activation; Stress; Nrf2; Pml; Vulnerability
ISSN (print) / ISBN
0950-9232
e-ISSN
0950-9232
Journal
Oncogene
Quellenangaben
Volume: 45,
Issue: 27,
Pages: 2727-2742
Publisher
Springer
Publishing Place
The Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status
Peer reviewed
Institute(s)
Institute of Lung Health and Immunity (LHI)
Grants
DIP-DFG grant (DIP) 529726222 DFG-GRK 2243, (MED) German Cancer Aid via grants 70112491 and 70114554 DFG, German Research Foundation-TRR 387/1- 514894665 MED
Flinkman-Marandy cancer research grant Rappaport institute translational grant #057-02 Project Grant from the ICRF PG-25-1463844
DIP-DFG grant (DIP)529726222
Flinkman-Marandy cancer research grant Rappaport institute translational grant #057-02 Project Grant from the ICRF PG-25-1463844
DIP-DFG grant (DIP)529726222