Cell Chemical Biology

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3 days ago

ER-localized ceramide accumulation contributes to replicative senescence Chitkara et al. propose a mechanistic link between disrupted ceramide trafficking and replicative senescence. Chitkara et al. demonstrate that impaired ceramide transport can lead to ER-localized ceramide accumulation, promoting ER stress and senescence. These findings establish ceramide metabolism trafficking as a key regulatory axis in replicative senescence.

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Cell Chemical Biology

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4 days ago

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins In this study, Gustafsen et al. introduce SORTACs, a PROTAC-like strategy that hijacks the sortilin-progranulin pathway to drive lysosomal degradation of extracellular proteins. SORTACs enable modular, small molecule and biologic degraders, expanding targeted protein degradation beyond the cytosol to previously inaccessible extracellular targets.

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Cell Chemical Biology

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5 days ago

Too much of a good thing: Promotion of tumor progression and metastasis by apoptotic cells Most tumor therapies induce the apoptotic pathway in tumor and bystander cells, but apoptotic cells may paradoxically enhance tumor growth and metastasis. Hagan et al. consider the tumor-promoting effects of apoptotic cells and discuss approaches to overcome these effects.

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Peter Kenny

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1 week ago

Opportunity in lead discovery biology at TRIANA Biomedicines (Boston MA USA) #MolBiol #biochem #CellBiol #ChemBiol 🧪
trianabio.com/job-posting-...

Cell Chemical Biology

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1 week ago

Receptor-ubiquitination-targeting antibody-drug conjugates for enhanced endocytosis and lysosomal delivery Zhuang et al. address limited antibody-drug conjugates (ADCs) internalization by developing ubitaADCs that harness receptor ubiquitination. By engaging membrane E3 ligases, ubitaADCs promote receptor endocytosis and lysosomal trafficking, enhancing intracellular payload delivery and supporting a modular strategy applicable to multiple tumor-associated receptors.

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Cell Chemical Biology

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1 week ago

Engineered pistol ribozymes selectively target KRAS G12V with enhanced efficacy by capping modification Liu et al. engineer a catalytic pistol ribozyme that selectively targets the KRAS p.G12V mutant transcript. By tuning ribozyme–substrate recognition and introducing a 5′ capping strategy, the authors achieve sustained and allele-specific KRAS silencing, highlighting programmable ribozymes as a precise RNA-targeting modality for oncogenic mutations.

Online now! Online now! Engineered pistol ribozymes selectively target KRAS G12V with enhanced efficacy by capping modification #chembiol

Cell Chemical Biology

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1 week ago

Control of the signaling of RAS proteins by modulating their palmitoylation Zhu et al. report an approach to reversibly control protein S-palmitoylation by fusing the depalmitoylase APT1 to target proteins. Using RAS proteins, they show that this approach enables the dynamic modulation of RAS palmitoylation and membrane localization by an APT1 inhibitor, and offers a platform for screening RAS palmitoyltransferase inhibitors.

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Cell Chemical Biology

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2 weeks ago

Transcending cell death – The diverse roles of necroptosis signal adaptors in pathogen infection Viruses are widely believed to evade host cell necroptosis to maximize their survival within the host. Huang, Li, and Chan challenge this paradigm by proposing that the host senses viral interference of necroptosis to tune the host response against the invading pathogen.

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Cell Chemical Biology

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2 weeks ago

De novo design of Ras isoform selective binders Zhang et al. use deep learning-based protein design to create isoform-specific Ras binders that selectively target the disordered C termini. These tools enable precise dissection of Ras isoform functions and uncover distinct Ras dependencies that emerge during RasG12C inhibitor resistance.

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Cell Chemical Biology

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2 weeks ago

Discovery of MARK2 as a physiological kinase for PER2 in the mammalian clock Phosphorylation of PER2 at serine 662 regulates circadian timing, and its serine to glycine G (S662G) mutation causes familial advanced sleep phase syndrome. Liu et al. identify MARK2 as the physiological S662 kinase through biochemical purification. MARK2 stabilizes PER2 to regulate the circadian rhythm, and its loss in mice exhibits phase advancement and period shortening.

Online now! Online now! Discovery of MARK2 as a physiological kinase for PER2 in the mammalian clock #chembiol

Cell Chemical Biology

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3 weeks ago

A small molecule PTER-selective inhibitor reduces food intake and body weight Targeting of non-incretin pathways for obesity remains a major therapeutic goal. Fu et al. solved the first PTER crystal structures and developed the first selective and in vivo-active PTER inhibitor. This inhibitor provides proof-of-concept data that the pharmacological targeting of PTER could be a viable non-incretin strategy for body weight control.

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Cell Chemical Biology

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3 weeks ago

Cytoplasmic tail diversity determines the effector bias of the adhesion GPCR ADGRL2 Adhesion GPCRs combine cell adhesion with intracellular signaling effector engagement to control an array of biological processes. How aGPCRs coordinate main effectors including G proteins, arrestins, and kinases is unclear. Garbett et al. examine the mechanisms of aGPCR signaling and find that tissue-specific sequence diversity controls effector bias.

Online now! Online now! Cytoplasmic tail diversity determines the effector bias of the adhesion GPCR ADGRL2 #chembiol

Cell Chemical Biology

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3 weeks ago

Influenza A virus polymerase co-opts distinct sets of host proteins for RNA transcription or replication Influenza A virus hijacks host proteins to support its life cycle, including factors co-opted to the viral polymerase. Rasmussen et al. identify distinct sets of host factors that support polymerase replication or transcription activity, revealing potential new antiviral targets.

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Cell Chemical Biology

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1 month ago

Intracellular cyclization-coupled peptide library screening yields potent transcription factor antagonists Brennan et al. integrate chemical peptide cyclization with live-cell screening, expanding the functional chemical space accessible to intracellular genetically encoded peptide libraries. The approach delivers functional cyclic peptide inhibitors of the oncogenic transcription factor CREB1, illustrating a general strategy for targeting transcription factor-DNA interactions previously considered “undruggable.”

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Madeline Kavanagh

@mads-chem.bsky.social

1 month ago

ABPP2027 The 15th International Activity-Based Protein Profiling Meeting will be held in Naturalis, Leiden, The Netherlands from June 2nd to 4th, 2027. This meeting will discuss the latest advancements in prot...

Save the date! 15th Activity Based Protein Profiling meeting #ABPP2027 is in Leiden, 2-4th June 2027. Join the mailing list for program updates and rego: www.universiteitleiden.nl/en/science/led3/abpp2027
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Cell Chemical Biology

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1 month ago

Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells Pang et al. identify a unique CD8+ T cell state (Tpeec) induced by NQO1-mediated redox cycling. They demonstrate that lawsone treatment redirects glucose flux into the pentose phosphate pathway, simultaneously enhancing T cell stemness and mitochondrial fitness. This metabolic rewiring improves the efficacy of adoptive T cell therapy against solid tumors.

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Cell Chemical Biology

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1 month ago

Lysosome-targeting chimeras enable targeted protein degradation Bozhao Li et al. review lysosome-targeting chimeras (LYTACs) as a transformative strategy for degrading extracellular and membrane proteins. They outline receptor-guided design principles, endocytic routing mechanisms, and translational challenges, highlighting how LYTACs expand targeted protein degradation beyond the proteasome.

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Cell Chemical Biology

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1 month ago

Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS van Tienen et al. develop CysMAP, a systematic cysteine scanning and covalent screening platform that maps druggable protein pockets. Applied to KRAS(G12D), CysMAP uncovers a novel pocket between switch-II and α3 whose covalent engagement stabilizes a distinct KRAS conformation, expanding strategies for targeting oncogenic RAS.

Online now! Online now! Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS #chembiol

Cell Chemical Biology

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1 month ago

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis Kim and Hergott et al. uncover a metabolic foundation for the pathogenic inflammation arising from TET2-mutant clonal hematopoiesis (CH). In myeloid cells, TET2 loss disinhibits the nutrient sensor/glycosyltransferase OGT, driving aberrant and inflammatory lipid accumulation via the metabolic enzyme ACLY. Inhibiting ACLY offers a therapeutic strategy for controlling CH-related hyperinflammation.

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Cell Chemical Biology

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1 month ago

Discovery of bioactive peptidoglycan fragments from Lactobacillaceae that confer intestinal protection in hosts Liang et al. quantified and profiled natural peptidoglycan fragments (PGNs) released by a panel of bacterial species. They found that prolonged exposure to Lactobacillaceae-derived PGNs induced tolerance in murine macrophages to subsequent TLR stimulation. They demonstrated that the intraperitoneal administration of the natural PGN GM-AQK protected mice against DSS-induced colitis.

Online now! Online now! Discovery of bioactive peptidoglycan fragments from Lactobacillaceae that confer intestinal protection in hosts #chembiol

Cell Chemical Biology

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1 month ago

Mechanosensation promotes broad-spectrum antiviral defense through membrane remodeling Huang et al. define the mechano-antiviral response system (MARS) and reveal that mechanical force triggers Piezo1-dependent membrane stiffening. This establishes a broad-spectrum, interferon-independent antiviral defense that can be exploited by small-molecule agonists or vibration.

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Cell Chemical Biology

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2 months ago

Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation Liu et al. reveal that lactate, an aerobic glycolysis product, promotes NLRP3 inflammasome activation and pyroptosis. NLRP3 is identified as a target of lactylation, and K24 and K565 have potential to facilitate inflammasome activation. In vivo, lactate inhibition attenuates inflammatory responses in polymicrobial sepsis model.

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Cell Chemical Biology

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2 months ago

The HEAT repeat protein MROH7 regulates the inflammatory macrophage response via LBP acetylation Regulating macrophage-mediated inflammation is critical for treating inflammatory disorders. Zhang et al. find MROH7 inhibits IL-1β via Arachidonic acid-dependent LBP acetylation/degradation, suppressing NF-κB signaling, highlighting MROH7 as a therapeutic target.

Online now! Online now! The HEAT repeat protein MROH7 regulates the inflammatory macrophage response via LBP acetylation #chembiol

Cell Chemical Biology

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2 months ago

Advances in degradomics technologies to assess proteolytic cleavage events Ziegler et al. outline how modern proteomics and mass spectrometry enable precise identification of protease-generated cleavage sites. They highlight enrichment-based and enrichment-free degradomics workflows used to map N- and C-terminal peptides, define protease specificity, and uncover substrate networks that drive health and disease.

Online now! Online now! Advances in degradomics technologies to assess proteolytic cleavage events #chembiol

Cell Chemical Biology

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2 months ago

Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO Lindsey et al. integrate structural studies with activity-based protein profiling to characterize a druggable pocket proximal to the RNA-binding interface of NONO that can be covalently targeted by low-reactivity chlorofluoroacetamide ligands to remodel the transcriptomes and suppress the growth of cancer cells.

Online now! Online now! Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO #chembiol

Cell Chemical Biology

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2 months ago

Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities Ke et al. review emerging proximity-inducing modalities—phosphorylation-targeting chimera, including PhosTACs, DEPTACs, PhoRCs, and PHICS—that modulate protein phosphorylation via an “event-driven” mechanism. They highlight how these bifunctional approaches offer a different avenue for phosphorylation-targeted therapeutics development, discussing recent applications and challenges in this field.

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Cell Chemical Biology

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2 months ago

Online now! Online now! Structural basis for NONO-specific modification by the α-chloroacetamide compound (R)-SKBG-1 #chembiol

Cell Chemical Biology

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2 months ago

Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia Uible et al. revealed a non-catalytic role for CASP1 in leukemia. Acting as a scaffolding hub for mTORC1-NF-κB signaling through RPTOR, CASP1 was essential for leukemic cell function. A CASP1-targeted PROTAC exposed this scaffolding activity as a therapeutic vulnerability in myeloid malignancies.

Online now! Online now! Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia #chembiol

Cell Chemical Biology

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2 months ago

Redundant or resilient? A systems view of ferroptosis surveillance mechanisms Liang et al. outline how cells deploy coordinated surveillance mechanisms, including the GPX4 axis, radical trapping antioxidants, and lipid remodeling pathways, to prevent ferroptosis across cellular organelles and tissues. This review provides a coherent framework for understanding ferroptotic vulnerability in health and disease and highlights opportunities for therapeutic intervention.

Online now! Online now! Redundant or resilient? A systems view of ferroptosis surveillance mechanisms #chembiol

Cell Chemical Biology

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2 months ago

Fluorogenic CRISPR for DNA imaging in live mammalian cells Fluorogenic bioimaging offers low background and high contrast, improving sensitivity and accuracy. Wan et al. review CRISPR-based genomic DNA imaging tools with fluorogenic capabilities, including split fluorescent proteins, fluorogenic aptamers, proteins, and molecular beacons. They compare the advantages and disadvantages of these approaches and identify key areas for further research.

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