Target and tissue selectivity of PROTAC degraders

Abstract

In this review, we focus on recent progress towards making selective PROTAC molecules and new PROTAC technologies that will continue to push the boundaries of achieving target and tissue selectivity.

Chemistries of bifunctional PROTAC degraders

“…Firstly, it may be that the expression levels of different types of E3 ligases in different cells are different, resulting in the different efficiency in degradation activities. 25 Secondly, it may be that different target proteins have certain E3 ligase selectivity, resulting in different efficiency of E3 ligase-induced protein ubiquitination and degradation effects. Finally, it may be the number and types of the PROTACs based on different E3 ligases are not enough so that the degraders designed based on a certain type of E3 ligase cannot induce the degradation of the related proteins.…”

“…In some cases, PROTACs exhibited better degradation activity and selectivity than small molecule inhibitors. 25 What's more, PROTACs exhibit some properties that small molecules do not have or are difficult to achieve, such as degradation of protein complexes, and “undruggable” targets. In this section, we introduce the design development and application of PROTACs based on some representative examples.…”

“…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).…”

Methods to characterize and discover molecular degraders in cells

“…Full description of these ligands and the ternary complexes mediated by the molecules requires the combination of multiple methods both in vitro and in live cells, especially given the need for high target and tissue selectivity. 38 In this review, we will cover technologies for measuring the ternary complex in vitro and in live cells and for discovering new targets induced by candidate degrader modalities. We first review phenotype-dependent assays, affinity-purification methods and global proteomics, and then focus on cellular approaches for discovering targets of molecular degraders, including chemical proteomics, enzymatic proximity labelling, fluorescent protein engineering, thermal shift profiling, and limited proteolysis.…”

Key Considerations in Targeted Protein Degradation Drug Discovery and Development

“…There are more than 600 E3 ubiquitin ligases encoded by the human genome, but only 2% of them have been applied in proximity-induced protein degradation. E3 ligases beyond VHL and CRBN for targeted protein degradation, for example, tissue-specific or disease-specific E3 ligases would considerably expand the application of targeted protein degradation for therapeutic purposes ( Kannt and Đikić 2021 ; Guenette et al, 2022 ). Systematic searching for E3 ubiquitin ligases and their ligands is achieved using chemoproteomics methods applying cysteine reactive covalent small molecules to map the E3 ligase proteome.…”