2. Academic Validation
  3. Reversing an agonist into an inhibitor: Development of mTOR degraders

Reversing an agonist into an inhibitor: Development of mTOR degraders

  • Eur J Med Chem. 2025 Sep 15:294:117774. doi: 10.1016/j.ejmech.2025.117774.
Liquan Zhu 1,  Siyi Fu 2,  Longfei Ma 2,  Zhe Chen 2,  Qian Zeng 2,  Ruichen Li 2,  Yiyu Zhou 2,  Huijuan Qian 2,  Xuli Meng 3,  Jingyan Ge 4
Affiliations

Affiliations

  • 1 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, PR China; General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, PR China.
  • 2 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, PR China.
  • 3 General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, PR China. Electronic address: mxlmail@126.com.
  • 4 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, PR China. Electronic address: gejy@zju.edu.cn.
PMID: 40398155 DOI: 10.1016/j.ejmech.2025.117774
Abstract

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for modulating protein function. In this study, we developed mTOR-targeting PROTACs by conjugating the mTOR agonist MHY-1485 to the Cereblon (CRBN) ligand pomalidomide, demonstrating that even activators can serve as effective warheads for targeted protein degradation. Through systematic screening, we identified PD-M6 as a potent bifunctional molecule capable of degrading mTOR (DC50 = 4.8 μM), reversing the proliferative effects of MHY-1485, and inhibiting cell proliferation (IC50 = 11.3 μM) while inducing Autophagy, akin to the mTOR known inhibitor rapamycin. Proteomic analysis further revealed that PD-M6 downregulated key proteins in the mTOR signaling pathway, including LAMTOR1, MAPKAP1, and CASTOR1, which are involved in proteasome-mediated degradation, cell division, Apoptosis, and lysosomal signaling. Notably, PD-M6 specifically induced the degradation of LAMTOR1. These findings highlight a novel approach for designing PROTACs from agonists, broadening the scope of targeted protein degradation strategies for therapeutic applications.

Keywords

Autophagy; Degradation; PROTACs; Proteomics; mTOR.

Figures
Products