About this Research Topic
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules based on the combination of ubiquitin E3 ligase ligands with an inhibitor of the protein of interest (POI) via different types of linkers. With this design, the protein of interest can be degraded, which may have different biological effects compared to classical inhibition. This technique has some advantages, as it can be used for undruggable targets. In addition, PROTACs act in very low concentrations and they can provide increased selectivity for the target of interest rather than the original small molecule inhibitor. Most recently developed PROTACs use one of the four ubiquitin E3 ligases: MDM2, Inhibitor of Apoptosis Protein (IAP), Von Hippel Lindau (VHL) Factor, and Cereblon (CRBN) binders. Such compounds were designed to target various targets and recently, two compounds (ARV-110 and ARV-471) have entered clinical trials.
The design, synthesis, and biological evaluation of PROTACs are challenging. Numerous and well-planned steps are needed for their chemical synthesis. Meanwhile, extensive biological evaluation is required to prove the ternary complex formation and the PROTACs’ degradation activity on the POI. To rationalize the biological activity, X-ray structures of the ternary complexes (as recently solved for some bromodomains) can provide important information. Alternatively, the ternary complex formation can be virtually predicted, which is still challenging and requires techniques like protein-protein docking.
In this Research Topic, the aim is to bring together cutting-edge research describing the design and synthesis of PROTACs targeting any protein of interest. The focus will be put on reports where a detailed biological activity related to the degradation of the protein of interest is described and compared to the effect shown by the original inhibitor. Of great interest are recent advances regarding X-ray crystallography of PROTAC/E3ligase/POI ternary complexes, molecular modelling and studying the mechanism of action of PROTACs, whether they are novel or show a novel application and biological activity.
The Topic Editors encourage submissions of Original Research, Review, Mini Review and Perspective articles that address, but are not limited to, the following themes:
• Proteolysis Targeting Chimeras (PROTACs)
• E3 Ligase Inhibitors
• Protein Degradation by PROTACs
• Ternary complex formation mediated by PROTACs
• Molecular modelling studies to design PROTACs
• Assay techniques to study PROTACs in vitro
Keywords: PROTACS, Ubiquitin E3 Ligase inhibitors, Protein Degradation
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