Developing potent PROTACs tools for selective degradation of HDAC6 protein.
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ABSTRACT:
SUBMITTER: An Z
PROVIDER: S-EPMC6626596 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Developing potent PROTACs tools for selective degradation of HDAC6 protein.
An Zixuan Z Lv Wenxing W Su Shang S Wu Wei W Rao Yu Y
Protein & cell 20190801 8
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Project description:The proteolysis targeting chimeras (PROTACs) technology has been rapidly developed since its birth in 2001, attracting rapidly growing attention of scientific institutes and pharmaceutical companies. At present, a variety of small molecule PROTACs have entered the clinical trial. However, as small molecule PROTACs flourish, non-small molecule PROTACs (NSM-PROTACs) such as peptide PROTACs, nucleic acid PROTACs and antibody PROTACs have also advanced considerably over recent years, exhibiting the unique characters beyond the small molecule PROTACs. Here, we briefly introduce the types of NSM-PROTACs, describe the advantages of NSM-PROTACs, and summarize the development of NSM-PROTACs so far in detail. We hope this article could not only provide useful insights into NSM-PROTACs, but also expand the research interest of NSM-PROTACs.
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Project description:Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors. Proteolysis-targeting chimera (PROTAC) technology can be used to target proteins by hijacking the ubiquitin-proteasome system. Conceptually, PROTAC aims to target the "undruggable" majority of proteins in the human proteome. Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades, TPD has expanded from theoretical studies to clinical strategies, with practical applications in oncological, immunological, and other diseases. In this review, we introduce the mechanisms, features, and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials. We also discuss PROTAC derivatives and other TPD strategies, such as lysosome-targeting chimeras, autophagy-targeting chimeras, and molecular glue strategies. Collectively, the studies summarized herein support the full potential of TPD in the biomedical industry.
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Project description:PROteolysis-TArgeting Chimeras (PROTACs) is an emerging and promising approach to target intracellular proteins for ubiquitination-mediated degradation, including those so-called undruggable protein targets, such as transcriptional factors and scaffold proteins. To date, plenty of PROTACs have been developed to degrade various disease-relevant proteins, such as estrogen receptor (ER), androgen receptor (AR), RTK, and CDKs. However, the on-target off-tissue and off-target effect is one of the major limitation that prevents the usage of PROTACs in clinic. To this end, we and several other groups have recently developed light-controllable PROTACs, as the representative for the third generation controllable PROTACs, by using either photo-caging or photo-switch approaches. In this review, we summarize the emerging light-controllable PROTACs and the prospective for other potential ways to achieve temporospatial control of PROTACs.
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