Theranostics 2024; 14(4):1464-1499. doi:10.7150/thno.92526 This issue Cite

Review

Degraders in epigenetic therapy: PROTACs and beyond

Xing-Jie Dai3, Shi-Kun Ji3, Meng-Jie Fu3, Gao-Zhi Liu3, Hui-Min Liu3, Shao-Peng Wang3, Liang Shen3, Ning Wang5, Piet Herdewijn3,4,6, Yi-Chao Zheng3,4, Sai-Qi Wang1,2✉, Xiao-Bing Chen1,2✉

1. Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, China.
2. Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, China.
3. Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
4. XNA platform, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
5. The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
6. Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Herestraat 49-Box 1041, 3000 Leuven, Belgium.

Citation:
Dai XJ, Ji SK, Fu MJ, Liu GZ, Liu HM, Wang SP, Shen L, Wang N, Herdewijn P, Zheng YC, Wang SQ, Chen XB. Degraders in epigenetic therapy: PROTACs and beyond. Theranostics 2024; 14(4):1464-1499. doi:10.7150/thno.92526. https://www.thno.org/v14p1464.htm
Other styles

File import instruction

Abstract

Graphic abstract

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)—encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies—have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.

Keywords: PROTACs, epigenetics, anti-cancer, drug design, protein degrader


Citation styles

APA
Dai, X.J., Ji, S.K., Fu, M.J., Liu, G.Z., Liu, H.M., Wang, S.P., Shen, L., Wang, N., Herdewijn, P., Zheng, Y.C., Wang, S.Q., Chen, X.B. (2024). Degraders in epigenetic therapy: PROTACs and beyond. Theranostics, 14(4), 1464-1499. https://doi.org/10.7150/thno.92526.

ACS
Dai, X.J.; Ji, S.K.; Fu, M.J.; Liu, G.Z.; Liu, H.M.; Wang, S.P.; Shen, L.; Wang, N.; Herdewijn, P.; Zheng, Y.C.; Wang, S.Q.; Chen, X.B. Degraders in epigenetic therapy: PROTACs and beyond. Theranostics 2024, 14 (4), 1464-1499. DOI: 10.7150/thno.92526.

NLM
Dai XJ, Ji SK, Fu MJ, Liu GZ, Liu HM, Wang SP, Shen L, Wang N, Herdewijn P, Zheng YC, Wang SQ, Chen XB. Degraders in epigenetic therapy: PROTACs and beyond. Theranostics 2024; 14(4):1464-1499. doi:10.7150/thno.92526. https://www.thno.org/v14p1464.htm

CSE
Dai XJ, Ji SK, Fu MJ, Liu GZ, Liu HM, Wang SP, Shen L, Wang N, Herdewijn P, Zheng YC, Wang SQ, Chen XB. 2024. Degraders in epigenetic therapy: PROTACs and beyond. Theranostics. 14(4):1464-1499.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image