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Trends in Pharmacological Sciences Nov 2023
Topics: Humans; Proteolysis
PubMed: 37832526
DOI: 10.1016/j.tips.2023.09.004 -
Future Medicinal Chemistry Apr 2022
Topics: Antiviral Agents; Proteolysis; Ubiquitination
PubMed: 35134309
DOI: 10.4155/fmc-2022-0005 -
Angewandte Chemie (International Ed. in... Mar 2024Many of the highest priority targets in a wide range of disease states are difficult-to-drug proteins. The development of reversible small molecule inhibitors for the... (Review)
Review
Many of the highest priority targets in a wide range of disease states are difficult-to-drug proteins. The development of reversible small molecule inhibitors for the active sites of these proteins with sufficient affinity and residence time on-target is an enormous challenge. This has engendered interest in strategies to increase the potency of a given protein inhibitor by routes other than further improvement in gross affinity. Amongst these, the development of catalytic protein inhibitors has garnered the most attention and investment, particularly with respect to protein degraders, which catalyze the destruction of the target protein. This article discusses the genesis of the burgeoning field of catalytic inhibitors, the current state of the art, and exciting future directions.
Topics: Proteins; Catalysis; Catalytic Domain; Proteolysis
PubMed: 38064411
DOI: 10.1002/anie.202316726 -
Cell Chemical Biology Jul 2021
Topics: Humans; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 34270936
DOI: 10.1016/j.chembiol.2021.06.011 -
Chemical Society Reviews May 2022Targeted protein degradation has emerged from the chemical biology toolbox as one of the most exciting areas for novel therapeutic development across the pharmaceutical... (Review)
Review
Targeted protein degradation has emerged from the chemical biology toolbox as one of the most exciting areas for novel therapeutic development across the pharmaceutical industry. The ability to induce the degradation, and not just inhibition, of target proteins of interest (POIs) with high potency and selectivity is a particularly attractive property for a protein degrader therapeutic. However, the physicochemical properties and mechanism of action for protein degraders can lead to unique pharmacokinetic (PK) and pharmacodynamic (PD) properties relative to traditional small molecule drugs, requiring a shift in perspective for translational pharmacology. In this review, we provide practical insights for building the PK-PD understanding of protein degraders in the context of translational drug development through the use of quantitative mathematical frameworks and standard experimental assays. Published datasets describing protein degrader pharmacology are used to illustrate the applicability of these insights. The learnings are consolidated into a translational PK-PD roadmap for targeted protein degradation that can enable a systematic, rational design workflow for protein degrader therapeutics.
Topics: Models, Biological; Proteolysis
PubMed: 35438107
DOI: 10.1039/d2cs00114d -
Basic Research in Cardiology Sep 2023Ischemic heart disease remains a leading cause of human mortality worldwide. One form of ischemic heart disease is ischemia-reperfusion injury caused by the... (Review)
Review
Ischemic heart disease remains a leading cause of human mortality worldwide. One form of ischemic heart disease is ischemia-reperfusion injury caused by the reintroduction of blood supply to ischemic cardiac muscle. The short and long-term damage that occurs due to ischemia-reperfusion injury is partly due to the proteolysis of diverse protein substrates inside and outside of cardiomyocytes. Ischemia-reperfusion activates several diverse intracellular proteases, including, but not limited to, matrix metalloproteinases, calpains, cathepsins, and caspases. This review will focus on the biological roles, intracellular localization, proteolytic targets, and inhibitors of these proteases in cardiomyocytes following ischemia-reperfusion injury. Recognition of the intracellular function of each of these proteases includes defining their activation, proteolytic targets, and their inhibitors during myocardial ischemia-reperfusion injury. This review is a step toward a better understanding of protease activation and involvement in ischemic heart disease and developing new therapeutic strategies for its treatment.
Topics: Humans; Proteolysis; Peptide Hydrolases; Myocardial Ischemia; Myocytes, Cardiac; Myocardial Reperfusion Injury
PubMed: 37768438
DOI: 10.1007/s00395-023-01007-z -
Chembiochem : a European Journal of... Dec 2023Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents....
Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4 recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4 recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4 neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4 molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.
Topics: Ubiquitin-Protein Ligases; Proteolysis
PubMed: 37418539
DOI: 10.1002/cbic.202300351 -
Biochemistry Jan 2020
Topics: Intercellular Signaling Peptides and Proteins; Peptides; Proteolysis
PubMed: 31538467
DOI: 10.1021/acs.biochem.9b00795 -
Genes Jan 2024DNA-protein crosslinks (DPCs) represent a unique and complex form of DNA damage formed by covalent attachment of proteins to DNA. DPCs are formed through a variety of... (Review)
Review
DNA-protein crosslinks (DPCs) represent a unique and complex form of DNA damage formed by covalent attachment of proteins to DNA. DPCs are formed through a variety of mechanisms and can significantly impede essential cellular processes such as transcription and replication. For this reason, anti-cancer drugs that form DPCs have proven effective in cancer therapy. While cells rely on numerous different processes to remove DPCs, the molecular mechanisms responsible for orchestrating these processes remain obscure. Having this insight could potentially be harnessed therapeutically to improve clinical outcomes in the battle against cancer. In this review, we describe the ways cells enzymatically process DPCs. These processing events include direct reversal of the DPC via hydrolysis, nuclease digestion of the DNA backbone to delete the DPC and surrounding DNA, proteolytic processing of the crosslinked protein, as well as covalent modification of the DNA-crosslinked proteins with ubiquitin, SUMO, and Poly(ADP) Ribose (PAR).
Topics: Ubiquitin; DNA Damage; Endonucleases; Hydrolysis; Proteolysis
PubMed: 38254974
DOI: 10.3390/genes15010085 -
Nature Chemical Biology Oct 2019Targeted protein degradation as a therapeutic modality has seen dramatic progress and massive investment in recent years because of the convergence of two key scientific... (Review)
Review
Targeted protein degradation as a therapeutic modality has seen dramatic progress and massive investment in recent years because of the convergence of two key scientific breakthroughs: optimization of first-generation peptidic proteolysis-targeted chimeras (PROTACs) into more drug-like molecules able to support in vivo proof of concept and the discovery that clinical molecules function as degraders by binding and repurposing the proteins cereblon and DCAF15. This provided clinical validation for the general approach through the cereblon modulator class of drugs and provided highly drug-like and ligand-efficient E3 ligase binders upon which to tether target-binding moieties. Increasingly rational and systematic approaches including biophysical and structural studies on ternary complexes are being leveraged as the field advances. In this Perspective we summarize the discoveries that have laid the foundation for future degradation therapeutics, focusing on those classes of small molecules that redirect E3 ubiquitin ligases to non-native substrates.
Topics: Binding Sites; Humans; Proteasome Endopeptidase Complex; Protein Binding; Proteolysis; Small Molecule Libraries; Ubiquitin-Protein Ligases
PubMed: 31527835
DOI: 10.1038/s41589-019-0362-y