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Updated: Jul 6, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Design, synthesis, and biological evaluation of RIPK1-targeting PROTACs
Hefeng Zhang1, Shuonan Zhang2,3, Tianchen Wang1,3
1Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
Abstract:
Cancer cells can hijack receptor-interacting protein kinase 1 (RIPK1) and exploit its scaffolding function to orchestrate pro-survival signaling and fuel immunosuppressive program. Accordingly, targeting RIPK1 for elimination has emerged as a promising anti-cancer strategy. Based on the RIPK1 inhibitor 4 previously reported by our group, we employed proteolysis targeting chimera (PROTAC) technology and designed a series of RIPK1 degraders. Structure-activity relationship (SAR) study revealed three types of ligands for E3 ligase - cereblon (CRBN), von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) - demonstrated varied efficacy in RIPK1 degradation of human and mouse cells. The VHL-based compound 18 exhibited potent RIPK1 degradation activity in both human and mouse cellular scenarios. Further biological evaluation confirmed that compound 18 potently induced RIPK1 degradation of I2.1 cells with a DC50 value of 274.4 nM and maintained long-term and dramatic RIPK1 degradation within 72 h. This study provided important insights into future development of RIPK1-PORTACs, and compound 18 was a promising RIPK1 degrader candidate.
Insights
Researchers developed novel proteolysis targeting chimera (PROTAC) molecules to degrade receptor-interacting protein kinase 1 (RIPK1), a key protein in cancer cell survival and immune suppression. Compound 18, a VHL-based degrader, showed potent RIPK1 degradation in various cancer cells, offering a promising new anti-cancer therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Receptor-interacting protein kinase 1 (RIPK1) is crucial for cancer cell pro-survival signaling and immune evasion.
- Targeting RIPK1 is a promising strategy for cancer therapy.
- Existing RIPK1 inhibitors can be enhanced using targeted protein degradation approaches.
Purpose of the Study:
- To design and synthesize novel RIPK1 degraders using proteolysis targeting chimera (PROTAC) technology.
- To investigate the structure-activity relationships (SAR) of different E3 ligase ligands in RIPK1 degradation.
- To evaluate the efficacy of a lead RIPK1 degrader candidate in cellular models.
Main Methods:
- Design and synthesis of RIPK1-targeting PROTACs utilizing various E3 ligase ligands (CRBN, VHL, IAP).
- Structure-activity relationship (SAR) studies to optimize RIPK1 degradation.
- Cellular assays to assess RIPK1 degradation efficacy (e.g., DC50 determination) and duration in human and mouse cancer cells.
Main Results:
- Multiple RIPK1 degraders were synthesized, with varied degradation efficiencies depending on the E3 ligase ligand.
- The von Hippel-Lindau (VHL)-based compound 18 demonstrated potent RIPK1 degradation across human and mouse cell lines.
- Compound 18 achieved significant RIPK1 degradation with a DC50 of 274.4 nM and sustained degradation for up to 72 hours.
Conclusions:
- RIPK1-targeting PROTACs represent a viable strategy for cancer therapy.
- Compound 18 is a highly effective RIPK1 degrader with potential for further preclinical development.
- This study provides valuable insights for the future design of RIPK1-PROTACs (RIPK1-PORTACs).
