Major Advances in Emerging Degrader Technologies

Abstract

Recently, degrader technologies have attracted increasing interest in the academic field and the pharmaceuticals industry. As one of the degrader technologies, proteolysis-targeting chimeras (PROTACs) have emerged as an attractive pharmaceutical development approach due to their catalytic ability to degrade numerous undruggable disease-causing proteins. Despite the remarkable progress, many aspects of traditional PROTACs still remain elusive. Its expansion could lead to PROTACs with new paradigm. Currently, many reviews focused on the design and optimization strategies through summarizing classical PROTACs, application in diseases and prospect of PROTACs. In this review, we categorize various emerging PROTACs ranging from simply modified classical PROTACs to atypical PROTACs such as nucleic acid-based PROTACs, and we put more emphasis on molecular design of PROTACs with different strategies. Furthermore, we summarize alternatives of PROTACs as lysosome-targeting chimeras (LYTACs) and macroautophagy degradation targeting chimeras (MADTACs) based on different degradation mechanism despite of lysosomal pathway. Beyond these protein degraders, targeting RNA degradation with the potential for cancer and virus therapeutics has been discussed. In doing so, we provide our perspective on the potential development or concerns of each degrader technology. Overall, we hope this review will offer a better mechanistic understanding of emerging degraders and prove as useful guide for the development of the coming degrader technologies.

Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)

“…Benefiting from the development of SELEX/Cell-SELEX for selected aptamers [ 206 , 207 ], this technology might allow more membrane protein-associated degradation than LYTAC. However, the stability and off-target effects of such aptamer chimeras need to be elucidated in further studies [ 208 ].…”

Degradation strategy of cyclin D1 in cancer cells and the potential clinical application

“…As for the application of ubiquitin mediated protein degradation, Luo et al. ( 78 ) reviewed major advances in PROteolysis TArgeting Chimeras (PROTAC), which mediates the transfer of poly-ubiquitin (Ub) chains from E3 ligase to the protein of interest (POI). At present, two powerful PROTAC candidates have entered phase 1/2 clinical trials developed by the Arvinas company, namely, ARV-110 targeting androgen receptors (AR) for treating prostate cancer ( 79 ), and ARV-471 targeting estrogen receptors (ER) for treating breast cancer ( 80 ).…”

Nanoparticle-mediated delivery of peptide-based degraders enables targeted protein degradation

“…The past decade has seen a surge in the development of protein degrading molecules, especially those targeting various oncoproteins. [1][2][3][4][5][6][7][8][9][10][11] PROTACs (PROteolysis TArgeting Chimeras) are heterobifunctional degraders that facilitate the selective degradation of a diverse array of intracellular proteins by hijacking the cell's own naturally occurring protein degradation mechanism -the ubiquitin-proteasome system (UPS). By employing a ligand that recruits an E3 ubiquitin ligase and another that binds a protein of interest (POI), PROTACs induce an artiUicial interaction between an E3 and a POI.…”