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Degraders in epigenetic therapy: PROTACs and beyond
Xing-Jie Dai1, Shi-Kun Ji1, Meng-Jie Fu1
1Key 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.
Theranostics
|February 23, 2024
Summary
Targeted protein degradation (TPD) offers new ways to target epigenetic proteins for cancer therapy. This review explores small-molecule degraders beyond PROTACs, highlighting their potential and challenges.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Epigenetics influences gene expression without altering DNA sequence, making it a key target for treating diseases like cancer.
- Existing epigenetic drugs face limitations including narrow applicability, toxicity, and resistance.
- Targeted Protein Degradation (TPD) strategies, including PROTACs, have advanced significantly.
Purpose of the Study:
- To review small-molecule degraders beyond PROTACs for epigenetic protein targets.
- To explore degradation mechanisms via proteasomal or lysosomal pathways.
- To discuss current challenges and future prospects in developing epigenetic drugs.
Main Methods:
- Comprehensive literature review of small-molecule degraders targeting epigenetic proteins.
- Analysis of various TPD strategies beyond PROTACs (e.g., molecular glues, dTAG).
- Examination of proteasomal and lysosomal degradation pathways for epigenetic targets.
Main Results:
- Small-molecule degraders offer alternative approaches to target epigenetic proteins, including bromodomain, histone acetylation/deacetylation, and methylation targets.
- These degraders utilize proteasomal or lysosomal pathways for protein elimination.
- The review highlights diverse TPD strategies beyond PROTACs.
Conclusions:
- Small-molecule degraders represent a promising frontier for developing novel epigenetic therapies.
- Overcoming challenges in potency, selectivity, and drug-likeness is crucial for clinical translation.
- Further research into TPD mechanisms can lead to more effective epigenetic drugs.
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