PROTACs: great opportunities for academia and industry

Abstract

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

Improving Precise CRISPR Genome Editing by Small Molecules: Is there a Magic Potion?

“…Once a new target has been identified small molecules can be systematically designed against the target by modifying their catalytic activity or protein-protein interactions. In addition, advances in the development of new modalities such as PROteolysis TArgeting Chimeras (ProTacs) will extend the number of druggable targets [80].…”

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer

“…The designing of PROTACs has different limitations, including problems in isolation, reduced cell permeability, and off-target toxicity effects due to a low therapeutic index [ 22 , 23 , 24 ]. PROTACs act in a catalytic mode, which hampers their pharmacokinetic and pharmacodynamic evaluation.…”

Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

“…In contrast, advances in computational chemistry and novel technologies, including mass spectrometry and high-throughput screening, the development and success of specific E3 ligase and deubiquitinase inhibitors with more selective anti-cancer activity may be possible. These new technologies may enable the development of innovative therapeutic approaches that target protein-protein interactions, or co-opt the ubiquitin system, as is the case with protein-targeting chimeric molecules, which bind to protein and induce their proteasomal degradation (PROTACs) [ 166 ]. It is clear that the NFκB pathway is essential for the proliferation and survival of HNSCC, in vitro and in vivo.…”