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Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies
Xiaopeng Peng1, Zhihao Hu1, Limei Zeng2
1College of Pharmacy, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou 314000, China.
Abstract:
Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.
Insights
New epigenetic degraders show promise for cancer therapy, overcoming limitations of traditional inhibitors. This review covers design, efficacy, and challenges of these novel cancer drugs.
Area of Science:
- Oncology
- Epigenetics
- Drug Discovery
Background:
- Epigenetic pathways are crucial in cancer development and progression.
- Epigenetic inhibitors have shown limited efficacy and selectivity.
- Emerging epigenetic degraders offer new therapeutic strategies.
Purpose of the Study:
- To review novel epigenetic degrader strategies developed between 2017-2023.
- To focus on rational design, pharmacodynamics, pharmacokinetics, and clinical status.
- To provide insights into challenges and solutions for epigenetic degrader development.
Main Methods:
- Comprehensive literature review of epigenetic degraders (2017-2023).
- Analysis of rational design principles for PROTACs, molecular glues, and HyT degraders.
- Evaluation of preclinical and clinical data on epigenetic degraders targeting cancer proteins.
Main Results:
- Numerous epigenetic degraders targeting cancer have been discovered.
- Degraders demonstrate potential for improved efficacy and selectivity over inhibitors.
- Key structural and pharmacokinetic data for select epigenetic degraders are presented.
Conclusions:
- Epigenetic degraders represent a promising new class of cancer therapeutics.
- Understanding design, pharmacodynamics, and pharmacokinetics is crucial for development.
- Addressing challenges in drug design and development will enhance clinical translation.
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