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European Journal of Medicinal Chemistry Nov 2023Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone... (Review)
Review
Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1-8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs. HDAC-PROTACs surpass traditional HDAC inhibitors in many aspects, such as higher selectivity, more potent antiproliferative activity, and the ability to disrupt the enzyme-independent functions of a multifunctional protein and overcome drug resistance. Rationally designing HDAC-PROTACs is a main challenge in development because slight variations in chemical structure can lead to drastic effects on the efficiency and selectivity of the degradation. In the future, HDAC-PROTACs can potentially be involved in clinical research with the support of the increased amount of in vivo data, pharmacokinetic evaluation, and pharmacological studies.
Topics: Sirtuin 2; Histone Deacetylase Inhibitors; Proteolysis; Proteolysis Targeting Chimera
PubMed: 37607440
DOI: 10.1016/j.ejmech.2023.115746 -
Cell Chemical Biology Jul 2023The multi-step degradation process of PROteolysis TArgeting Chimeras (PROTACs) poses a challenge for their rational development, as the rate-limiting steps that...
The multi-step degradation process of PROteolysis TArgeting Chimeras (PROTACs) poses a challenge for their rational development, as the rate-limiting steps that determine PROTACs efficiency remain largely unknown. Moreover, the slow throughput of currently used endpoint assays does not allow the comprehensive analysis of larger series of PROTACs. Here, we developed cell-based assays using the NanoLuciferase and HaloTag that allow measuring PROTAC-induced degradation and ternary complex formation kinetics and stability in cells. Using PROTACs developed for the degradation of WD40 repeat domain protein 5 (WDR5), the characterization of the mode of action of these PROTACs in the early degradation cascade revealed a key role of ternary complex formation and stability. Comparing a series of ternary complex crystal structures highlighted the importance of an efficient E3-target interface for ternary complex stability. The developed assays outline a strategy for the rational optimization of PROTACs using a series of live cell assays monitoring key steps of the early PROTAC-induced degradation pathway.
Topics: Proteolysis; Proteins; Ubiquitin-Protein Ligases
PubMed: 37354907
DOI: 10.1016/j.chembiol.2023.06.002 -
ACS Chemical Biology Jul 2023PROteolysis TArgeting Chimeras (PROTACs) are of significant current interest for the development of probe molecules and drug leads. However, they suffer from certain...
PROteolysis TArgeting Chimeras (PROTACs) are of significant current interest for the development of probe molecules and drug leads. However, they suffer from certain limitations. PROTACs are rule-breaking molecules with sub-optimal cellular permeability, solubility, and other drug-like properties. In particular, they exhibit an unusual dose-response curve where high concentrations of the bivalent molecule inhibit degradation activity, a phenomenon known as the hook effect. This will likely complicate their use in vivo. In this study, we explore a novel approach to create PROTACs that do not exhibit a hook effect. This is achieved by equipping the target protein and E3 ubiquitin ligase ligands with functionalities that undergo rapid and reversible covalent assembly in cellulo. We report the development of Self-Assembled Proteolysis Targeting Chimeras that mediate the degradation of the Von Hippel-Lindau E3 ubiquitin ligase and do not evince a hook effect.
Topics: Proteolysis Targeting Chimera; Proteolysis; Ubiquitin-Protein Ligases; Proteins; Ligands
PubMed: 37422908
DOI: 10.1021/acschembio.3c00199 -
Cancer Letters Mar 2023Proteolysis-targeting chimeras (PROTACs) are being developed as an effective method for degrading cancer-related proteins by modifying the endogenous... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) are being developed as an effective method for degrading cancer-related proteins by modifying the endogenous ubiquitin-proteasome system. To investigate the dynamics between an E3 ligase and target protein, researchers have developed a wide variety of bifunctional PROTACs by combining small molecule ligands. These PROTACs employ numerous ligands, some of which are reversible, some of which are irreversible, some attach to orthosteric sites, while others bind to allosteric sites. Some are agonists, while others are antagonists, and the target protein may be activated in either a positive or negative manner. A variety of targeted ligand approaches can be used to enhance PROTAC properties, including tumor selectivity and drug delivery, and to overcome drug resistance. The processes and behaviors of small molecule-based PROTACs and targeted proteolysis approaches as anticancer therapeutic molecules have been introduced in this mini-review.
Topics: Humans; Ligands; Neoplasms; Proteasome Endopeptidase Complex; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 36642326
DOI: 10.1016/j.canlet.2023.216065 -
Cell and Tissue Research Aug 2021Proteases play a central role in regulating renal pathophysiology and are increasingly evaluated as actionable drug targets. Here, we review the role of proteolytic... (Review)
Review
Proteases play a central role in regulating renal pathophysiology and are increasingly evaluated as actionable drug targets. Here, we review the role of proteolytic systems in inflammatory kidney disease. Inflammatory kidney diseases are associated with broad dysregulations of extracellular and intracellular proteolysis. As an example of a proteolytic system, the complement system plays a significant role in glomerular inflammatory kidney disease and is currently under clinical investigation. Based on two glomerular kidney diseases, lupus nephritis, and membranous nephropathy, we portrait two proteolytic pathomechanisms and the role of the complement system. We discuss how profiling proteolytic activity in patient samples could be used to stratify patients for more targeted interventions in inflammatory kidney diseases. We also describe novel comprehensive, quantitative tools to investigate the entirety of proteolytic processes in a tissue sample. Emphasis is placed on mass spectrometric approaches that enable the comprehensive analysis of the complement system, as well as protease activities and regulation in general.
Topics: Animals; Humans; Inflammation; Kidney Glomerulus; Proteolysis
PubMed: 33864499
DOI: 10.1007/s00441-021-03433-8 -
Accounts of Chemical Research Apr 2021One of the biggest bottlenecks in modern drug discovery efforts is in tackling the undruggable proteome. Currently, over 85% of the proteome is still considered... (Review)
Review
One of the biggest bottlenecks in modern drug discovery efforts is in tackling the undruggable proteome. Currently, over 85% of the proteome is still considered undruggable because most proteins lack well-defined binding pockets that can be functionally targeted with small molecules. Tackling the undruggable proteome necessitates innovative approaches for ligand discovery against undruggable proteins as well as the development of new therapeutic modalities to functionally manipulate proteins of interest. Chemoproteomic platforms, in particular activity-based protein profiling (ABPP), have arisen to tackle the undruggable proteome by using reactivity-based chemical probes and advanced quantitative mass spectrometry-based proteomic approaches to enable the discovery of "ligandable hotspots" or proteome-wide sites that can be targeted with small-molecule ligands. These sites can subsequently be pharmacologically targeted with covalent ligands to rapidly discover functional or nonfunctional binders against therapeutic proteins of interest. Chemoproteomic approaches have also revealed unique insights into ligandability such as the discovery of unique allosteric sites or intrinsically disordered regions of proteins that can be pharmacologically and selectively targeted for biological modulation and therapeutic benefit. Chemoproteomic platforms have also expanded the scope of emerging therapeutic modalities for targeted protein degradation and proteolysis-targeting chimeras (PROTACs) through the discovery of several new covalent E3 ligase recruiters. Looking into the future, chemoproteomic approaches will unquestionably have a major impact in further expansion of existing efforts toward proteome-wide ligandability mapping, targeted ligand discovery efforts against high-value undruggable therapeutic targets, further expansion of the scope of targeted protein degradation platforms, the discovery of new molecular glue scaffolds that enable unique modulation of protein function, and perhaps most excitingly the development of next-generation small-molecule induced-proximity-based therapeutic modalities that go beyond degradation. Exciting days lie ahead in this field as chemical biology becomes an increasingly major driver in drug discovery, and chemoproteomic approaches are sure to be a mainstay in developing next-generation therapeutics.
Topics: Drug Discovery; Humans; Ligands; Proteolysis; Proteome; Proteomics
PubMed: 33733731
DOI: 10.1021/acs.accounts.1c00065 -
Cell Chemical Biology Jul 2021Molecular glues and proteolysis targeting chimeras (PROTACs) have emerged as small-molecule tools that selectively induce the degradation of a chosen protein and have... (Review)
Review
Molecular glues and proteolysis targeting chimeras (PROTACs) have emerged as small-molecule tools that selectively induce the degradation of a chosen protein and have shown therapeutic promise. Recently, several approaches employing light as an additional stimulus to control induced protein degradation have been reported. Here, we analyze the principles guiding the design of such systems, provide a survey of the literature published to date, and discuss opportunities for further development. Light-responsive degraders enable the precise temporal and spatial control of protein levels, making them useful research tools but also potential candidates for human precision medicine.
Topics: Humans; Precision Medicine; Proteins; Proteolysis; Small Molecule Libraries
PubMed: 34115971
DOI: 10.1016/j.chembiol.2021.05.010 -
Future Medicinal Chemistry Jan 2022Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC-PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC-PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.
Topics: Drug Design; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Molecular Conformation; Proteolysis
PubMed: 34951318
DOI: 10.4155/fmc-2021-0206 -
Molecules (Basel, Switzerland) Aug 2022Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively... (Review)
Review
Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.
Topics: Drug Development; Immunotherapy; Neoplasms; Proteolysis
PubMed: 36080223
DOI: 10.3390/molecules27175439 -
The Alkaloids. Chemistry and Biology 2023The 2,5-diketopiperazine (DKP) motif is present in many biologically relevant, complex natural products. The cyclodipeptide substructure offers structural rigidity and... (Review)
Review
The 2,5-diketopiperazine (DKP) motif is present in many biologically relevant, complex natural products. The cyclodipeptide substructure offers structural rigidity and stability to proteolysis that makes these compounds promising candidates for medical applications. Due to their fascinating molecular architecture, synthetic organic chemists have focused significant effort on the total synthesis of these compounds. This review covers many such efforts on the total synthesis of DKP containing complex alkaloid natural products.
Topics: Proteolysis; Diketopiperazines; Alkaloids; Biological Products
PubMed: 37716796
DOI: 10.1016/bs.alkal.2023.06.002