Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation.

Background: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness.

Methods: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders.

O-GlcNAcase regulates pluripotency states of human embryonic stem cells.

Understanding the regulation of human embryonic stem cells (hESCs) pluripotency is critical to advance the field of developmental biology and regenerative medicine. Despite the recent progress, molecular events regulating hESC pluripotency, especially the transition between naive and primed states, still remain unclear. Here we show that naive hESCs display lower levels of O-linked N-acetylglucosamine (O-GlcNAcylation) than primed hESCs.

A Computational and Chemical Design Strategy for Manipulating Glycan-Protein Recognition.

Glycans are complex biomolecules that encode rich information and regulate various biological processes, such as fertilization, host-pathogen binding, and immune recognition, through interactions with glycan-binding proteins. A key driving force for glycan-protein recognition is the interaction between the π electron density of aromatic amino acid side chains and polarized C─H groups of the pyranose (termed the CH-π interaction). However, the relatively weak binding affinity between glycans and proteins has hindered the application of glycan detection and imaging.

Discovery of highly potent and selective KRAS degraders by VHL-recruiting PROTACs for the treatment of tumors with KRAS-Mutation.

Although several covalent KRAS inhibitors have made great progress in the treatment of KRAS-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRAS Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRAS-dependent cancer cells growth with nanomolar IC and DC values, and ＞ 95 % maximum degradation (D).

Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with alterations.

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely and based on thalidomide and tepotinib.

O-GlcNAcylation promotes pancreatic tumor growth by regulating malate dehydrogenase 1.

Oncogenic Kras-activated pancreatic ductal adenocarcinoma (PDAC) cells highly rely on an unconventional glutamine catabolic pathway to sustain cell growth. However, little is known about how this pathway is regulated. Here we demonstrate that Kras mutation induces cellular O-linked β-N-acetylglucosamine (O-GlcNAc), a prevalent form of protein glycosylation.

O-GlcNAcylation regulates epidermal growth factor receptor intracellular trafficking and signaling.

SignificanceEpidermal growth factor receptor (EGFR) is one of the most important membrane receptors that transduce growth signals into cells to sustain cell growth, proliferation, and survival. EGFR signal termination is initiated by EGFR internalization, followed by trafficking through endosomes, and degradation in lysosomes. How this process is regulated is still poorly understood.

Spatiotemporal Activation of Protein O-GlcNAcylation in Living Cells.

O-linked -acetylglucosamine (O-GlcNAc) is a prevalent protein modification that plays fundamental roles in both cell physiology and pathology. O-GlcNAc is catalyzed solely by O-GlcNAc transferase (OGT). The study of protein O-GlcNAc function is limited by the lack of tools to control OGT activity with spatiotemporal resolution in cells.

[Advances in technologies for large-scale enrichment and identification of ribonucleic acid-protein complexes].

Ribonucleic acid (RNA) rarely exists alone in the cell. RNAs interact with a variety of proteins and form RNA-protein complexes (RP-complexes) in every step of their life cycle, from transcription to degradation. These RP-complexes play key roles in regulating a variety of physiological processes.

An Ultrafast Glycoproteome Analysis Method Using Thermoresponsive Magnetic Fluid-Immobilized Enzymes.

Glycosylation is one of the most common and important post-translational modification methods, and it plays a vital role in controlling many biological processes. Increasing discovery of abnormal alterations in linked glycans associated with many diseases leads to greater demands for rapid and efficient glycosylation profiling in large-scale clinical samples. In the workflow of global glycosylation analysis, enzymatic digestion is the main rate-limiting step, and it includes both protease digestion and peptide-4-(-acetyl-beta-glucosaminyl) asparagine amidase (PNGase) F deglycosylation.

A new tandem enrichment strategy for the simultaneous profiling of -GlcNAcylation and phosphorylation in RNA-binding proteome.

RNA-protein interactions play important roles in almost every step of the lifetime of RNAs, such as RNA splicing, transporting, localization, translation and degradation. Post-translational modifications, such as O-GlcNAcylation and phosphorylation, and their "cross-talk" (OPCT) are essential to the activity and function regulation of RNA-binding proteins (RBPs). However, due to the extremely low abundance of O-GlcNAcylation and the lack of RBP-targeted enrichment strategies, large-scale simultaneous profiling of O-GlcNAcylation and phosphorylation on RBPs is still a challenging task.

A facile "one-material" strategy for tandem enrichment of small extracellular vesicles phosphoproteome.

Small extracellular vesicles (SEVs), are cell-derived, membrane-enclosed nanometer-sized vesicles that play vital roles in many biological processes. Recent years, more and more evidences proved that small EVs have close relationship with many diseases such as cancers and Alzheimer's disease. The use of phosphoproteins in SEVs as potential biomarkers is a promising new choice for early diagnosis and prognosis of cancer.

Novel Two-Dimensional MoS-Ti Nanomaterial for Efficient Enrichment of Phosphopeptides and Large-Scale Identification of Histidine Phosphorylation by Mass Spectrometry.

Due to its key roles in regulating the occurrence and development of cancer, protein histidine phosphorylation has been increasingly recognized as an important form of post-translational modification in recent years. However, large-scale analysis of histidine phosphorylation is much more challenging than that of serine/threonine or tyrosine phosphorylation, mainly because of its acid lability. In this study, MoS-Ti nanomaterials were synthesized using a solvothermal method and taking advantage of the electrostatic adsorption between MoS nanosheets and Ti.