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.
- 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: [email protected].
- 4. Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, PR China. Electronic address: [email protected].
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.