2. Academic Validation
  3. Design, synthesis, and activity evaluation of RET protein degradation based on PROTAC and HyTTD techniques

Design, synthesis, and activity evaluation of RET protein degradation based on PROTAC and HyTTD techniques

  • Bioorg Med Chem Lett. 2026 Jun:135:130588. doi: 10.1016/j.bmcl.2026.130588.
Ning Xu 1,  Yunmeng Zhao 2,  Jinfeng Liu 1,  Zhenyu Mao 1,  Haonan Feng 1,  Tingting Zhang 1,  Jialin Yu 1,  Yaxia Yuan 3,  Xiabin Chen 4,  Ting Qiu 5,  Lei Ma 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
  • 2 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 3 Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
  • 4 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: [email protected].
  • 5 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: [email protected].
  • 6 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: [email protected].
PMID: 41692312 DOI: 10.1016/j.bmcl.2026.130588
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.

Keywords

Hydrophobic tag tethering degraders; Proteolysis-targeting chimeras; Rearranged during transfection; Targeted protein degradation.

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