2. Academic Validation
  3. Mighty mini-PROTACs: an emerging class of degraders

Mighty mini-PROTACs: an emerging class of degraders

  • Eur J Med Chem. 2026 Jan 5:301:118202. doi: 10.1016/j.ejmech.2025.118202.
Xiao Chen 1,  Kefan Liao 1,  Jiawei Yuan 1,  Jianchao Zhang 2,  Hai Rao 3
Affiliations

Affiliations

  • 1 Department of Biochemistry, Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 2 Department of Biochemistry, Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China. Electronic address: [email protected].
  • 3 Department of Biochemistry, Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China; Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China. Electronic address: [email protected].
PMID: 41075608 DOI: 10.1016/j.ejmech.2025.118202
Abstract

Proteolysis-targeting chimera (PROTAC) is an emerging therapeutic strategy that rewires the ubiquitin-proteasome system to destroy pathogenic proteins. Despite tremendous progress, PROTACs still face significant challenges in their development and clinical application. The historically first and simplest degradation signal is a single amino acid, leading to the N-end rule proteolytic pathway, but its PROTAC adaptation has been under-explored. Here, we examine the feasibility of the N-end rule pathway in addressing some major issues in the field and introduce the resulting mini-PROTACs bearing small, diverse, and interchangeable degrons. Such an approach potentially helps overcome resistance issues associated with existing ubiquitin ligases as well as helps enhance drug-like properties. Finally, we discuss the advantages and limitations of mini-PROTACs compared to Other classical PROTACs, which will facilitate their clinical applications.

Keywords

Amino acids; Degron; Linker-free; N-end rule pathway; PROTAC; Ubiquitin ligase; mini-PROTAC.

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