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Drug Discovery Today Nov 2023Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad... (Review)
Review
Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad range of substrates and the potential to degrade intracellular and extracellular proteins, protein aggregates, damaged organelles and non-protein molecules. Thus, they hold great promise for drug R&D. This study has focused on the biogenesis of lysosomes, their basic functions, lysosome-associated diseases and targeted protein degradation technologies through the lysosomal pathway. In addition, we thoroughly examine the potential applications and limitations of this technology and engage in insightful discussions on potential avenues for future research. Our primary objective is to foster preclinical research on this technology and facilitate its successful clinical implementation.
Topics: Proteolysis; Lysosomes; Proteins; Autophagy
PubMed: 37708931
DOI: 10.1016/j.drudis.2023.103767 -
Molecular Therapy : the Journal of the... Jul 2023The function and significance of RAS proteins in cancer have been widely studied for decades. In 2013, the National Cancer Institute established the RAS Initiative to... (Review)
Review
The function and significance of RAS proteins in cancer have been widely studied for decades. In 2013, the National Cancer Institute established the RAS Initiative to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes and to create effective therapies for RAS-driven cancers. This initiative spurred researchers to develop novel approaches and to discover small molecules targeting this protein that was at one time termed "undruggable." More recently, advanced efforts in RAS degraders including PROTACs, linker-based degraders, and direct proteolysis degraders have been explored as novel strategies to target RAS for cancer treatment. These RAS degraders present new opportunities for RAS therapies and may prove fruitful in understanding basic cell biology. Novel delivery strategies will further enhance the efficacy of these therapeutics. In this review, we summarize recent efforts to develop RAS degraders, including PROTACs and E3 adaptor and ligase fusions as cancer therapies. This review also details the direct RAS protease degrader, RAS/RAP1-specific endopeptidase that directly and specifically cleaves RAS.
Topics: Humans; Neoplasms; Proteolysis; Proteins; Endopeptidases; ras Proteins; Ubiquitin-Protein Ligases
PubMed: 36945775
DOI: 10.1016/j.ymthe.2023.03.017 -
Nature Communications Jan 2024Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how...
Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson's Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes' capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model.
Topics: Humans; Parkinson Disease; Proteostasis; Astrocytes; Proteolysis; Mesencephalon; Organoids; Lysosomes
PubMed: 38200091
DOI: 10.1038/s41467-024-44732-2 -
Trends in Pharmacological Sciences Nov 2023
Topics: Humans; Proteolysis
PubMed: 37832526
DOI: 10.1016/j.tips.2023.09.004 -
Nature Communications Jan 2024Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for...
Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.
Topics: Carrier Proteins; Proteolysis; Ubiquitin; Ubiquitin-Protein Ligases; Proteolysis Targeting Chimera
PubMed: 38177131
DOI: 10.1038/s41467-023-44237-4 -
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 -
Theranostics 2024Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently... (Review)
Review
Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.
Topics: United States; Humans; Histones; Protein Processing, Post-Translational; Proteolysis; Epigenesis, Genetic; Lysosomes; Neoplasms, Squamous Cell
PubMed: 38389844
DOI: 10.7150/thno.92526 -
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 -
Seminars in Cell & Developmental Biology Mar 2024Executioner caspases are evolutionarily conserved regulators of cell death under apoptotic stress. Activated executioner caspases drive apoptotic cell death through... (Review)
Review
Executioner caspases are evolutionarily conserved regulators of cell death under apoptotic stress. Activated executioner caspases drive apoptotic cell death through cleavage of diverse protein substrates or pyroptotic cell death in the presence of gasdermin E. On the other hand, activation of executioner caspases can also trigger pro-survival and pro-proliferation signals. In recent years, a growing body of studies have demonstrated that cells can survive from executioner caspase activation in response to stress and that the survivors undergo molecular and phenotypic alterations. This review focuses on death and survival from executioner caspase activation, summarizing the role of executioner caspases in apoptotic and pyroptotic cell death and discussing the potential mechanism and consequences of survival from stress-induced executioner caspase activation.
Topics: Apoptosis; Cell Death; Caspases; Proteolysis; Protein Processing, Post-Translational; Caspase 8
PubMed: 37468421
DOI: 10.1016/j.semcdb.2023.07.005