Targeted protein degradation in cancer: strategies for undruggable targets and progress towards clinical translation.
12 affiliations
- 1Department of Orthopedics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
- 2National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- 3Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Changsha, Hunan, 410011, China.
- 4Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- 5Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, China.
- 6FuRong Laboratory, Changsha, Hunan, 410078, China.
- 7Department of Orthopedics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. [email protected].
- 8National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China. [email protected].
- 9Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Changsha, Hunan, 410011, China. [email protected].
- 10Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China. [email protected].
- 11Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, China. [email protected].
- 12FuRong Laboratory, Changsha, Hunan, 410078, China. [email protected].
Abstract
Targeted protein degradation (TPD) has significantly influenced cancer therapy by enabling the targeting of traditionally undruggable oncogenic drivers such as transcription factors, chromatin remodelers, and mediators of protein-protein interactions, overcoming limitations of conventional inhibitors. This approach harnesses endogenous cellular machinery, specifically the ubiquitin-proteasome system and lysosomal pathways, to achieve precise and efficient elimination of pathogenic proteins. Currently, one degradation-based agent, vepdegestrant, has been approved by FDA, while most agents remain in Phase I or II evaluation, representing significant progress in addressing previously intractable targets in cancers. Nevertheless, a substantial number of disease-relevant proteins remain challenging to modulate effectively. This review focuses on undruggable targets in cancer and distinguishes three target categories: 1) Structurally undruggable targets; 2) Formerly undruggable, now inhibitor-accessible but degradation offers a mechanistic advantage; 3) Non-enzymatic targets. We highlight recent advances in the development of TPD strategies against these elusive targets to a cutoff of 30 September 2026, with the aim of providing a more systematic theoretical foundation for the broader application of the developing TPD in cancer therapeutics.
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BibTeX
@article{tang2026targeted,
title = {{Targeted protein degradation in cancer: strategies for undruggable targets and progress towards clinical translation.}},
author = {Jinxin Tang and Zehao Cheng and Tiancheng Xie and Yan Zhuang and Hongkun Hu and Chenbei Li and Hua Wang and Chengyao Feng and Chao Tu},
journal = {Biomarker research},
year = {2026},
month = oct,
doi = {10.1186/s40364-026-01032-9},
url = {https://europepmc.org/article/MED/42958559},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Targeted protein degradation in cancer: strategies for undruggable targets and progress towards clinical translation.
AU - Jinxin Tang
AU - Zehao Cheng
AU - Tiancheng Xie
AU - Yan Zhuang
AU - Hongkun Hu
AU - Chenbei Li
AU - Hua Wang
AU - Chengyao Feng
AU - Chao Tu
PY - 2026
DA - 2026/10/28
JO - Biomarker research
DO - 10.1186/s40364-026-01032-9
UR - https://europepmc.org/article/MED/42958559
AB - Targeted protein degradation (TPD) has significantly influenced cancer therapy by enabling the targeting of traditionally undruggable oncogenic drivers such as transcription factors, chromatin remodelers, and mediators of protein-protein interactions, overcoming limitations of conventional inhibitors. This approach harnesses endogenous cellular machinery, specifically the ubiquitin-proteasome system and lysosomal pathways, to achieve precise and efficient elimination of pathogenic proteins. Currently, one degradation-based agent, vepdegestrant, has been approved by FDA, while most agents remain in Phase I or II evaluation, representing significant progress in addressing previously intractable targets in cancers. Nevertheless, a substantial number of disease-relevant proteins remain challenging to modulate effectively. This review focuses on undruggable targets in cancer and distinguishes three target categories: 1) Structurally undruggable targets; 2) Formerly undruggable, now inhibitor-accessible but degradation offers a mechanistic advantage; 3) Non-enzymatic targets. We highlight recent advances in the development of TPD strategies against these elusive targets to a cutoff of 30 September 2026, with the aim of providing a more systematic theoretical foundation for the broader application of the developing TPD in cancer therapeutics.
SN - 2050-7771
ER -