Linker-free PROTACs efficiently induce the degradation of oncoproteins

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.

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Publication Details

Journal
Nature Communications
Published
2025-05-23
DOI
https://doi.org/10.1038/s41467-025-60107-7
Citations
19
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
15.31

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article

Linker-free PROTACs efficiently induce the degradation of oncoproteins

Jianchao Zhang, Xiaoxiao Song, Huiyong Sun, Xiao Chen et al.
19 citations
Nature Communications
Protein Degradation and Inhibitors
15.31
article

Linker-free PROTACs efficiently induce the degradation of oncoproteins

Jianchao Zhang, Xiaoxiao Song, Huiyong Sun, Xiao Chen, Hai Rao, Tingjun Hou, Chaowei Liu, Chris Soon Heng Tan, Lijing Fang, Congli Chen, Fengming Li, Ming-Yuan Su, Kefan Liao
article en
19 citations

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.

Nature CommunicationsVol. 16(1)
China Pharmaceutical University (CN), Southern University of Science and Technology (CN), Shenzhen Institutes of Advanced Technology (CN), Zhejiang University (CN)
National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Southern University of Science and Technology, Shenzhen Fundamental Research Program, National Key Research and Development Program of China
Openalex Percentile: Top 1%
Protein Degradation and Inhibitors
15.31
DOIOpen Access PDFOpenAlex
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