期刊
PHARMACOLOGICAL RESEARCH
卷 172, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2021.105804
关键词
Bromodomain; Selective inhibitors; PROTAC degraders; Molecular mechanism
资金
- Macau Science and Technology Development Fund [0015/2019/AMJ, 001/2020/ALC]
- National Natural Science Foundation of China [82000074]
- Scientific Research Funding Project of Education Department of Liaoning Province [jyt-dldxjc202005]
- Science and Technology Innovation Fund Project of Dalian [2020JJ27SN071]
Research has shown that although bromodomain-containing proteins exhibit high structural similarity, individual bromodomains have distinct functions and can lead to different cellular phenotypes after pharmacological inhibition. Significant progress has been made in developing bromodomain-selective inhibitors targeting BET and non-BET proteins, enriching the knowledge base for bromodomain-selective drug discovery.
Bromodomain-containing proteins include bromodomain and extra-terminal (BET) and non-BET families. Due to the conserved bromodomain (BD) module between BD-containing proteins, and especially BETs with each member having two BDs (BD1 and BD2), the high degree of structural similarity makes BD-selective inhibitors much difficult to be designed. However, increasing evidences emphasized that individual BDs had distinct functions and different cellular phenotypes after pharmacological inhibition, and selectively targeting one of the BDs could result in a different efficacy and tolerability profile. This review is to summarize the pioneering progress of BD-selective inhibitors targeting BET and non-BET proteins, focusing on their structural features, biological activity, therapeutic application and experimental/theoretical mechanisms. The present proteolysis targeting chimeras (PROTAC) degraders targeting BDs, and clinical status of BD-selective inhibitors were also analyzed, providing a new insight into future direction of bromodomain-selective drug discovery.
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