PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Abstract

PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

Chemistries of bifunctional PROTAC degraders

“…86–88 Given the good drug-like properties of CRBN ligands, thalidomide and its analogs are widely used in the design and synthesis of PROTACs. 18,23 In 2015, Bradner et al reported the first case of the protein degrader dBET1 by recruiting CRBN E3 ligase (Fig. 4D).…”

“…5A). 18,23 The remaining several E3 ligases were developed by later researchers and are currently used in a narrow scope. The main reasons are as follows: the first point is that some new ligands are derived from natural products, and their structures are relatively complex making them difficult to be synthesized and used in large quantities.…”

“…to design PROTACs, such as BRD4, BTK, HDAC, etc. 18,23 Some proteins are less tolerant to E3 ligase and only a certain E3 ligase (CRBN or VHL) can be used to design PROTACs, such as Aurora A, FKBP12, etc. 18,23 The reasons for these differences are mainly due to the following points.…”

“…According to the latest statistics in February 2022, PROTACs can induce the degradation of more than 130 target proteins, including cancer, immune disorders, viral infections, neurodegenerative diseases, etc. 18,20–25 As the first protein-degrading drug company, Arvinas recently disclosed the structure and clinical data for the androgen receptor (AR) degrader ARV-110 (NCT03888612) and the estrogen receptor (ERα) degrader ARV-471 (NCT04072952) (Fig. 1C).…”

Small-Molecule PROTACs for Cancer Immunotherapy

“…To this end, this review gathered the application of PROTACs for immune-related targets in recent three years ( Table 1 ), including the PD-1/PD-L1 checkpoint and its regulatory pathways (SHP2 and BET), vital processes in tumorigenesis such as metabolism (IDO1), epigenetic modification (HDAC), and apoptosis (Bcl-2 family), as well as immuno-modulating signals (STAT3 and MAPK), and also some targets which have not or rarely treated by PROTAC molecules (CD47, Foxp3, COX-1/2, NAMPT, and TGF-β1). It should be noted that most of these targets and PROTACs were summarized by Rao et al in recent reviews [ 28 , 37 ]. Thus, this review will specifically focus on the immunological consequences after the degradation/inhibition of these targets, aiming to bias the development of small-molecule PROTACs for immunomodulation rather than simple tumor killing.…”