2. Academic Validation
  3. Identification of RET PROTAC with excellent degradation efficiency against medullary thyroid carcinoma

Identification of RET PROTAC with excellent degradation efficiency against medullary thyroid carcinoma

  • Eur J Med Chem. 2026 Oct 5:315:118928. doi: 10.1016/j.ejmech.2026.118928.
Jaewon Song 1,  Sugene Lim 1,  Eunhye Jeon 2,  Chanil Kim 3,  Seung Min Park 4,  Jong Bae Park 5,  Taebo Sim 6
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
  • 3 OmixAI Co., Ltd., 43 Janghan-ro, Dongdaemun-gu, Seoul, 02629, Republic of Korea.
  • 4 Department of Medicine, Kyung Hee University School of Medicine, 26 Kyunghee-daero, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
  • 5 OmixAI Co., Ltd., 43 Janghan-ro, Dongdaemun-gu, Seoul, 02629, Republic of Korea; Department of Medicine, Kyung Hee University School of Medicine, 26 Kyunghee-daero, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
  • 6 Department 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; Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address: [email protected].
PMID: 42161102 DOI: 10.1016/j.ejmech.2026.118928
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.

Keywords

Medullary thyroid cancer; PROTAC; RET; Targeted protein degradation.

Figures
Products