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

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.

Graphical abstract

Figure 1

(A) Protein degradation mechanism mediated by PROTACs; (B) In RTK activated cells, degradation mechanism of target proteins mediated by phosphoPROTACs.

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

(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).