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Review
. 2022 Jul;12(7):2990-3005.
doi: 10.1016/j.apsb.2022.02.022. Epub 2022 Feb 26.

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

Sinan Ma  1 , Jianai Ji  1 , Yuanyuan Tong  1 , Yuxuan Zhu  1 , Junwei Dou  1 , Xian Zhang  1 , Shicheng Xu  1 , Tianbao Zhu  1 , Xiaoli Xu  1   2 , Qidong You  1   2 , Zhengyu Jiang  1   2
Affiliations
Review

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

Sinan Ma et al. Acta Pharm Sin B. 2022 Jul.

Abstract

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.

Keywords: Antibody PROTACs; Non-small molecule PROTACs; Nucleic acid PROTACs; Peptide PROTACs; Protein degradation.

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Figures

Image 1
Graphical abstract
Figure 1
Figure 1
(A) Protein degradation mechanism mediated by PROTACs; (B) In RTK activated cells, degradation mechanism of target proteins mediated by phosphoPROTACs.
Figure 2
Figure 2
Degradation mechanism of target proteins mediated by nucleic acid PROTACs. (A) Degradation mechanism of target proteins mediated by TF PROTACs; (B) Degradation mechanism of target proteins mediated by RNA-PROTACs and G4-PROTAC; (C) Degradation mechanism of target proteins mediated by aptamer–PROTACs.
Figure 3
Figure 3
(A) Degradation mechanism of target proteins mediated by different types of antibody PROTACs; (B) XIAP-based PROTAC for targeted degradation of ERα (PROTAC 5) and VHL-based PROTAC for targeted degradation of ERα (PROTAC 6); (C) Three ligation strategies for coupling antibodies to small molecules; (D) Structure of trastuzumab–PROTAC conjugate (Ab–PROTAC 3).
See this image and copyright information in PMC

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