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Updated: May 22, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Identification of RET PROTAC with excellent degradation efficiency against medullary thyroid carcinoma
Jaewon Song1, Sugene Lim1, Eunhye Jeon2
1Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
Abstract:
Mutations and rearrangements of Rearranged during Transfection kinase (RET) are highly implicated with thyroid cancer. This study aimed to explore the therapeutic potential of a targeted protein degradation (TPD) strategy against RET-associated medullary thyroid carcinoma (MTC). The investigation of the structure-activity relationship (SAR) led to the identification of a novel RET-CRBN degrader, JW15 which possesses excellent degradation capability (DC50 = 0.3 nM) and potent anti-proliferative activity (GI50 = 1.2 nM) on TT cells (MTC). Mechanistic studies revealed that JW15 degrades RET kinase via the ubiquitin-proteasome system (UPS) and effectively recruits cereblon (CRBN) E3 ligase in target engagement assays. Notably, JW15 exhibited superior suppression of RET phosphorylation and downstream signaling compared with selpercatinib. In addition, JW15 demonstrated greater efficacy than selpercatinib in inducing apoptosis and suppressing colony-forming capacity on TT cells, particularly at a concentration of 1 nM. JW15 administered intravenously at 20 mg/kg twice weekly demonstrated significant antitumor efficacy, showing 70% tumor growth inhibition in RET Ba/F3 xenograft models over 13 days. Taken together, our study provides fundamental guidelines for structure-guided design and optimization for the development of RET degraders, offering a promising strategy for targeting RET-driven cancers.
Insights
A novel targeted protein degradation strategy using JW15 effectively degrades RET kinase in medullary thyroid carcinoma cells. This approach shows superior efficacy over existing treatments and significant antitumor activity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Mutations in Rearranged during Transfection (RET) kinase are key drivers of thyroid cancer, particularly medullary thyroid carcinoma (MTC).
- Targeted protein degradation (TPD) offers a novel therapeutic strategy by hijacking the cell's natural degradation machinery.
Purpose of the Study:
- To investigate the therapeutic potential of a TPD strategy targeting RET in MTC.
- To identify and characterize a novel RET degrader with potent anti-cancer activity.
Main Methods:
- Structure-activity relationship (SAR) studies to design a novel RET-CRBN degrader (JW15).
- In vitro assays to assess degradation capability (DC50), anti-proliferative activity (GI50), and target engagement via cereblon (CRBN) E3 ligase recruitment.
- Comparison of JW15 with selpercatinib in cell-based assays and in vivo xenograft models.
Main Results:
- JW15 demonstrated high degradation capability (DC50 = 0.3 nM) and potent anti-proliferative activity (GI50 = 1.2 nM) against MTC cells.
- JW15 effectively degraded RET via the ubiquitin-proteasome system (UPS) and outperformed selpercatinib in suppressing RET phosphorylation and downstream signaling.
- JW15 showed superior efficacy in inducing apoptosis and inhibiting colony formation, and achieved significant tumor growth inhibition (70%) in vivo.
Conclusions:
- JW15 represents a promising novel therapeutic agent for RET-driven cancers, including MTC.
- The study provides guidelines for structure-guided design of RET degraders.
- TPD strategy targeting RET offers a potent alternative to traditional kinase inhibitors.
