Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies.
10.1016/j.apsb.2023.09.003
- Author:
Xiaopeng PENG
1
;
Zhihao HU
1
;
Limei ZENG
2
;
Meizhu ZHANG
1
;
Congcong XU
1
;
Benyan LU
1
;
Chengpeng TAO
1
;
Weiming CHEN
1
;
Wen HOU
1
;
Kui CHENG
3
;
Huichang BI
3
;
Wanyi PAN
1
;
Jianjun CHEN
3
Author Information
1. College of Pharmacy, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou 314000, China.
2. College of Basic Medicine, Gannan Medical University, Ganzhou 314000, China.
3. Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
- Publication Type:Review
- Keywords:
Degrader;
Epigenetic;
Hydrophobic tagging;
Molecular glue;
PROTAC
- From:
Acta Pharmaceutica Sinica B
2024;14(2):533-578
- CountryChina
- Language:English
-
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.
