Discovery of ferroptosis-inducing R4VP compounds for targeting aggressive cancers

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• Aggressive and therapy-resistant cancers pose significant treatment challenges and are linked to poor patient survival.
• RNF4, an E3 ubiquitin ligase, promotes cancer cell survival and tumorigenesis by stabilizing oncoproteins and aiding DNA repair.
• Elevated RNF4 levels correlate with poor prognosis in various cancers, including carcinomas, melanoma, and sarcoma.

Purpose of the Study:

• To design and develop novel dual degrader compounds (R4VPs) targeting RNF4 for cancer therapy.
• To investigate the mechanism of R4VPs in inducing cancer cell death.
• To evaluate the efficacy of R4VPs in therapy-resistant cancer models.

Main Methods:

• Design and synthesis of R4VPs, dual degraders linking Von Hippel-Lindau protein (VHL) with RNF4.
• Assessment of RNF4 degradation and oncoprotein levels upon R4VP treatment.
• Evaluation of R4VPs' effect on cancer cell viability and induction of ferroptosis, including interaction with GPX4.
• Testing R4VPs efficacy in cancer cells with specific mutations (EGFR, PI3K) and in resistant melanoma and sarcoma models.

Main Results:

• R4VPs successfully promote RNF4 degradation and reduce stabilized oncoproteins.
• R4VPs selectively induce ferroptosis in cancer cells, sparing normal cells.
• Ferroptosis induction by R4VPs is linked to GPX4 modification.
• R4VPs preferentially target cancer cells with EGFR pathway mutations and demonstrate efficacy in resistant melanoma and sarcoma cells.

Conclusions:

• R4VPs represent a novel therapeutic strategy by selectively inducing ferroptosis in cancer cells.
• Targeting RNF4 degradation offers a promising approach for treating aggressive and therapy-resistant cancers.
• The findings highlight the potential of R4VPs as a new class of drugs for difficult-to-treat malignancies.