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Updated: Feb 17, 2026
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Design, synthesis, and activity evaluation of RET protein degradation based on PROTAC and HyTTD techniques
Ning Xu1, Yunmeng Zhao2, Jinfeng Liu1
1Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Abstract:
Point mutations and fusions in the Rearranged during Transfection (RET) proto-oncogene are established drivers in diverse malignancies. Although selective RET inhibitors such as selpercatinib and pralsetinib have been clinically approved, the emergence of resistance mutations limits their durable efficacy, underscoring the need for novel therapeutic modalities. Targeted protein degradation (TPD), which harnesses the endogenous ubiquitin-proteasome system to induce protein degradation, provides a promising strategy to overcome resistance to traditional small-molecule inhibitors. In this study, we systematically evaluated two distinct TPD approaches, proteolysis-targeting chimeras (PROTACs) and hydrophobic tag tethering degraders (HyTTDs). We report the design and synthesis of the first RET-targeting HyTTD, compound B2, which achieves 91.4% degradation of CCDC6-RET fusion protein in TPC-1 cells at 10 μM within 48 h. These results not only validate hydrophobic tag tethering as a feasible strategy for RET degradation but also propose a new therapeutic direction for RET-driven cancers.
Insights
Researchers developed a novel hydrophobic tag tethering degrader (HyTTD) to target and degrade the RET fusion protein, offering a new therapeutic strategy for RET-driven cancers resistant to current treatments.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Rearranged during Transfection (RET) proto-oncogene alterations drive various cancers.
- Approved RET inhibitors face resistance, necessitating alternative therapies.
- Targeted protein degradation (TPD) offers a promising approach to overcome drug resistance.
Purpose of the Study:
- To evaluate proteolysis-targeting chimeras (PROTACs) and hydrophobic tag tethering degraders (HyTTDs) for RET degradation.
- To design and synthesize the first hydrophobic tag tethering degrader (HyTTD) targeting RET.
- To assess the efficacy of the novel HyTTD in degrading RET fusion proteins.
Main Methods:
- Systematic evaluation of two TPD strategies: PROTACs and HyTTDs.
- Design and synthesis of a novel RET-targeting HyTTD (compound B2).
- Assessment of compound B2's degradation activity against CCDC6-RET fusion protein in TPC-1 cells.
Main Results:
- Compound B2 demonstrated significant degradation of CCDC6-RET fusion protein.
- 91.4% degradation was achieved at 10 μM concentration within 48 hours in TPC-1 cells.
- Hydrophobic tag tethering was validated as a feasible strategy for RET degradation.
Conclusions:
- Hydrophobic tag tethering is a viable method for targeting RET degradation.
- The developed HyTTD represents a potential new therapeutic avenue for RET-driven malignancies.
- This study provides a foundation for developing novel TPD-based therapies against resistant cancers.
