Linker-free PROTACs efficiently induce the degradation of oncoproteins PMID: 40410168

ADC Targets in Oncology

2026-04-10

Linker-free PROTACs efficiently induce the degradation of oncoproteins

Nat Commun. 2025 May 23;16(1):4794. doi: 10.1038/s41467-025-60107-7.

Jianchao Zhang ^# ¹ , Congli Chen ^# ² , Xiao Chen ^# ¹ , Kefan Liao ¹ , Fengming Li ³ , Xiaoxiao Song ¹ , Chaowei Liu ¹ , Ming-Yuan Su ¹ ⁴ ⁵ ⁶ , Huiyong Sun ⁷ , Tingjun Hou ⁸ , Chris Soon Heng Tan ³ , Lijing Fang ⁹ , Hai Rao ¹⁰ ¹¹ ¹²

Affiliations

1. Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
2. Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, China.
3. Department of Chemistry, Southern University of Science and Technology, Shenzhen, China.
4. Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China.
5. Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, China.
6. SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
7. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China.
8. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
9. Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, China. [email protected].
10. Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China. [email protected].
11. Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China. [email protected].
12. SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China. [email protected].
# Contributed equally.

Abstract

Proteolysis-targeting chimeras (PROTACs) present a potentially effective strategy against various diseases via selective proteolysis. How to increase the efficacy of PROTACs remains challenging. Here, we explore the necessity of the linker, which has been deemed as an integral part of heterobifunctional PROTACs. Adopting single amino acid-based degradation signals, we find that the linker is not a required feature of the PROTACs. Notably, the linker-free PROTAC, Pro-BA, exhibits superior efficacy over its linker-bearing counterparts in degrading EML4-ALK and inhibiting lung Cancer cell growth, as Pro-BA induces a stronger interaction between the target and the E3 ubiquitin Ligase. Pro-BA is a water-soluble, orally administered degrader that significantly inhibits the tumor growth in a xenograft mouse model. The broad applicability of this linker-free PROTAC strategy is further validated through the development of Bcr-Abl degrader. Our study introduces a design paradigm for PROTACs, potentially facilitating the advancement of more efficient therapeutic degraders.