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Cell Death & Disease Aug 2023Metastatic colorectal cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs...
FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer.
Metastatic colorectal cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs for mCRC. Fucosyltransferase 8 (FUT8) is a potential therapeutic target with high level in most malignant cancers including CRC. FUT8 mediates the core fucosylation of CD276 (B7-H3), a key immune checkpoint molecule (ICM), in CRC. FUT8-silence-induced defucosylation at N104 on B7-H3 attracts heat shock protein family A member 8 (HSPA8, also known as HSC70) to bind with 106-110 SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway. Then we report the development and characterization of a potent and highly selective small-molecule inhibitor of FUT8, named FDW028, which evidently prolongs the survival of mice with CRC pulmonary metastases (CRPM). FDW028 exhibits potent anti-tumor activity by defucosylation and impelling lysosomal degradation of B7-H3 through the CMA pathway. Taken together, FUT8 inhibition destabilizes B7-H3 through CMA-mediated lysosomal proteolysis, and FDW028 acts as a potent therapeutic candidate against mCRC by targeting FUT8. FDW028, an inhibitor specifically targeted FUT8, promotes defucosylation and consequent HSC70/LAMP2A-mediated lysosomal degradation of B7-H3, and exhibits potent anti-mCRC activities.
Topics: Animals; Mice; Chaperone-Mediated Autophagy; Autophagy; Proteolysis; Lung Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Lysosomes
PubMed: 37537172
DOI: 10.1038/s41419-023-06027-0 -
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 -
Cell Host & Microbe Jul 2023Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically...
Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.
Topics: Humans; Antiviral Agents; Proteolysis; RNA, Viral; Ligands; Viruses; Ubiquitin-Protein Ligases; Viral Proteins; Carrier Proteins
PubMed: 37339625
DOI: 10.1016/j.chom.2023.05.030 -
Advanced Biology Dec 2023Protein degradation is a general process to maintain cell homeostasis. The intracellular protein quality control system mainly includes the ubiquitin-proteasome system... (Review)
Review
Protein degradation is a general process to maintain cell homeostasis. The intracellular protein quality control system mainly includes the ubiquitin-proteasome system and the lysosome pathway. Inspired by the physiological process, strategies to degrade specific proteins have developed, which emerge as potent and effective tools in biological research and drug discovery. This review focuses on recent advances in targeted protein degradation techniques, summarizing the principles, advantages, and challenges. Moreover, the potential applications and future direction in biological science and clinics are also discussed.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitination; Homeostasis
PubMed: 37518856
DOI: 10.1002/adbi.202300083 -
Nature Biotechnology Apr 2024Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we...
Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.
Topics: Animals; Mice; Mucins; Peptide Hydrolases; Neoplasms; Proteolysis
PubMed: 37537499
DOI: 10.1038/s41587-023-01840-6 -
Science (New York, N.Y.) Aug 2023Aubiquitin-independent pathway targets nuclear proteins to the proteasome.
Aubiquitin-independent pathway targets nuclear proteins to the proteasome.
Topics: Cytoplasm; Nuclear Proteins; Proteasome Endopeptidase Complex; Proteolysis; Genes, Immediate-Early; Humans; Animals; Mice
PubMed: 37616357
DOI: 10.1126/science.adj8230 -
Nature Chemical Biology Jan 2024Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds...
Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.
Topics: Cyclins; Ubiquitin-Protein Ligases; Proteolysis; Structure-Activity Relationship
PubMed: 37679459
DOI: 10.1038/s41589-023-01409-z -
European Journal of Medicinal Chemistry Jul 2023The gaining importance of Targeted Protein Degradation (TPD) and PROTACs (PROteolysis-TArgeting Chimeras) have drawn the scientific community's attention. PROTACs are... (Review)
Review
The gaining importance of Targeted Protein Degradation (TPD) and PROTACs (PROteolysis-TArgeting Chimeras) have drawn the scientific community's attention. PROTACs are considered bifunctional robots owing to their avidity for the protein of interest (POI) and E3-ligase, which induce the ubiquitination of POI. These molecules are based on event-driven pharmacology and are applicable in different conditions such as oncology, antiviral, neurodegenerative disease, acne etc., offering tremendous scope to researchers. In this review, primarily, we attempted to compile the recent works available in the literature on PROTACs for various targeted proteins. We summarized the design and development strategies with a focus on molecular information of protein residues and linker design. Rationalization of the ternary complex formation using Artificial Intelligence including machine & deep learning models and traditionally followed computational tools are also included in this study. Moreover, details describing the optimization of PROTACs chemistry and pharmacokinetic properties are added. Advanced PROTAC designs and targeting complex proteins, is summed up to cover the wide spectrum.
Topics: Humans; Proteolysis; Artificial Intelligence; Neurodegenerative Diseases; Robotics; Ubiquitin-Protein Ligases; Proteins
PubMed: 37119667
DOI: 10.1016/j.ejmech.2023.115384 -
Cell Communication and Signaling : CCS Sep 2023Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous... (Review)
Review
Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous mitochondria-dependent and exogenous death receptor pathways, and studies have shown that caspase-8-dependent external pathways appear to be more important than the activity of the intrinsic pathways. This paper reviews the regulation of anoikis by external pathways mediated by death receptors. Different death receptors bind to different ligands to activate downstream caspases. The possible mechanisms of Fas-associated death domain (FADD) recruitment by Fas and TNF receptor 1 associated-death domain (TRADD) recruitment by tumor necrosis factor receptor 1 (TNFR1), and DR4- and DR5-associated FADD to induce downstream caspase activation and regulate anoikis were reviewed. This review highlights the possible mechanism of the death receptor pathway mediation of anoikis and provides new insights and research directions for studying tumor metastasis mechanisms. Video Abstract.
Topics: Anoikis; Proteolysis; Caspases; Mitochondria; Protein Processing, Post-Translational
PubMed: 37667281
DOI: 10.1186/s12964-023-01247-5 -
Molecules (Basel, Switzerland) Dec 2023Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell... (Review)
Review
Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell Cyclin-dependent kinase (CDK) activation, is a key pathological mechanism in cancer. Recently, selective CDK4/6 inhibitors have shown clinical success, particularly in treating advanced-stage estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This review provides an in-depth analysis of the action mechanism and recent advancements in CDK4/6 inhibitors, categorizing them based on their structural characteristics and origins. Furthermore, it explores proteolysis targeting chimers (PROTACs) targeting CDK4/6. We hope that this review could be of benefit for further research on CDK4/6 inhibitors and PROTACs.
Topics: Humans; Female; Cyclin-Dependent Kinase 4; Proteolysis; Cyclin-Dependent Kinase 6; Protein Kinase Inhibitors; Breast Neoplasms
PubMed: 38138549
DOI: 10.3390/molecules28248060