Pub Date : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.008
Yusuf Z. Tufail , Carlos Guijas , David A. Kummer , Cassandra L. Henry , Jeanne V. Moody , Taylor Andalis , Bryan Boyd , Jacob Gil , Jacquelyn Ha , Dylan M. Herbst , Rachel A. Herbst-Graham , Clayton Hutton , Ellen M. Kozina , Micah J. Niphakis , Nhi Ngo , Gary P. O’Neill , Holly T. Reardon , Michael Shaghafi , Olesya A. Ulanovskaya , Nicholas Raffaele , Jason R. Clapper
Diacylglycerol lipase (DAGL) produces 2-arachidonoylglycerol (2-AG) and other proinflammatory lipids. Inactivation of DAGLs reduces the production of 2-AG, arachidonic acid (AA) and eicosanoids and elicits antinociceptive and anti-(neuro)inflammatory effects in rodents. However, inhibitors that enter the brain can cause significant central nervous system (CNS) side effects. Using activity-based protein profiling (ABPP), we report the discovery of A1480LS, a potent, in vivo active, small molecule dual inhibitor of DAGLα/β that is functionally biased to the periphery. We demonstrate that A1480LS reduces pain behaviors and nociceptor activity in animal models. Moreover, A1480LS accomplishes this by reducing 2-AG and other lipids in peripheral tissues without causing adverse CNS effects. Overall, we show that inhibiting DAG metabolism in the periphery elicits antinociceptive effects that can be functionally dissected from adverse central effects and provide preclinical validation for a non-narcotic strategy to treat pain.
{"title":"Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism","authors":"Yusuf Z. Tufail , Carlos Guijas , David A. Kummer , Cassandra L. Henry , Jeanne V. Moody , Taylor Andalis , Bryan Boyd , Jacob Gil , Jacquelyn Ha , Dylan M. Herbst , Rachel A. Herbst-Graham , Clayton Hutton , Ellen M. Kozina , Micah J. Niphakis , Nhi Ngo , Gary P. O’Neill , Holly T. Reardon , Michael Shaghafi , Olesya A. Ulanovskaya , Nicholas Raffaele , Jason R. Clapper","doi":"10.1016/j.chembiol.2025.12.008","DOIUrl":"10.1016/j.chembiol.2025.12.008","url":null,"abstract":"<div><div>Diacylglycerol lipase (DAGL) produces 2-arachidonoylglycerol (2-AG) and other proinflammatory lipids. Inactivation of DAGLs reduces the production of 2-AG, arachidonic acid (AA) and eicosanoids and elicits antinociceptive and anti-(neuro)inflammatory effects in rodents. However, inhibitors that enter the brain can cause significant central nervous system (CNS) side effects. Using activity-based protein profiling (ABPP), we report the discovery of A1480LS, a potent, <em>in vivo</em> active, small molecule dual inhibitor of DAGLα/β that is functionally biased to the periphery. We demonstrate that A1480LS reduces pain behaviors and nociceptor activity in animal models. Moreover, A1480LS accomplishes this by reducing 2-AG and other lipids in peripheral tissues without causing adverse CNS effects. Overall, we show that inhibiting DAG metabolism in the periphery elicits antinociceptive effects that can be functionally dissected from adverse central effects and provide preclinical validation for a non-narcotic strategy to treat pain.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 74-90.e19"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.chembiol.2025.10.013
Wenjin Wan , Xin Ji , Haozhi Song , Zhongxuan Zhang , Chun Kit Kwok , Xiaohong Fang , Xing Li
Spatiotemporal imaging of genomic DNA dynamics in live mammalian cells is essential for elucidating eukaryotic organization and processes relevant to health and disease. CRISPR systems greatly facilitate the development of live cell DNA imaging tools. However, conventional CRISPR imaging tools typically utilize constitutively fluorescent proteins, resulting in high background noise, nonspecific nucleolar signals, and low signal-to-noise ratios. To address this, fluorogenic CRISPR-based imaging tools have been developed. These tools remain non-fluorescent until they bind to the target DNA, thus significantly reducing the background and enhancing the sensitivity. This review summarizes four fluorogenic CRISPR strategies, each utilizing different fluorogenic reporters, including fluorogenic proteins, fluorogenic RNA aptamers, split fluorescent proteins, and molecular beacons. These fluorogenic CRISPR approaches successfully monitored the subnucleus gene loci localization, dynamics, and DNA breaks and repairs. We anticipate that this review can inspire researchers to expand the fluorogenic CRISPR for cellular DNA imaging and diverse bioapplications.
{"title":"Fluorogenic CRISPR for DNA imaging in live mammalian cells","authors":"Wenjin Wan , Xin Ji , Haozhi Song , Zhongxuan Zhang , Chun Kit Kwok , Xiaohong Fang , Xing Li","doi":"10.1016/j.chembiol.2025.10.013","DOIUrl":"10.1016/j.chembiol.2025.10.013","url":null,"abstract":"<div><div>Spatiotemporal imaging of genomic DNA dynamics in live mammalian cells is essential for elucidating eukaryotic organization and processes relevant to health and disease. CRISPR systems greatly facilitate the development of live cell DNA imaging tools. However, conventional CRISPR imaging tools typically utilize constitutively fluorescent proteins, resulting in high background noise, nonspecific nucleolar signals, and low signal-to-noise ratios. To address this, fluorogenic CRISPR-based imaging tools have been developed. These tools remain non-fluorescent until they bind to the target DNA, thus significantly reducing the background and enhancing the sensitivity. This review summarizes four fluorogenic CRISPR strategies, each utilizing different fluorogenic reporters, including fluorogenic proteins, fluorogenic RNA aptamers, split fluorescent proteins, and molecular beacons. These fluorogenic CRISPR approaches successfully monitored the subnucleus gene loci localization, dynamics, and DNA breaks and repairs. We anticipate that this review can inspire researchers to expand the fluorogenic CRISPR for cellular DNA imaging and diverse bioapplications.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 33-44"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.014
Ana M. Sebastião
In a study recently published in Nature, Yue et al.1 provide a causal relationship between mitochondrial metabolism, adenosine receptor signaling, and the mechanism of action for novel antidepressants. Their findings identify adenosine as a key driver of rapid-acting antidepressant effects and as a therapeutic target for major depressive disorder.
{"title":"Adenosine signaling as a hub for the action of novel antidepressant strategies","authors":"Ana M. Sebastião","doi":"10.1016/j.chembiol.2025.12.014","DOIUrl":"10.1016/j.chembiol.2025.12.014","url":null,"abstract":"<div><div>In a study recently published in <em>Nature</em>, Yue et al.<span><span><sup>1</sup></span></span> provide a causal relationship between mitochondrial metabolism, adenosine receptor signaling, and the mechanism of action for novel antidepressants. Their findings identify adenosine as a key driver of rapid-acting antidepressant effects and as a therapeutic target for major depressive disorder.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 7-9"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.009
Yucheng Guo , Zhenlin Ouyang , Wenbo He , Qian Qin , Jiaxin Zhang , Ting Yu , Min Jiao , Peter M. Hwang , Fang Zheng , Serge Muyldermans , Yurong Wen
Enterotoxigenic Bacteroides fragilis (ETBF) promotes colonic inflammation by secreting metalloenzyme toxins (BFTs). Understanding BFT mechanisms and developing neutralization strategies is critical. Here, we have solved the structures of BFT-1 and BFT-2, revealing that residue 357 in the active site of the catalytic domain explains the diversity of function observed in BFT subtypes. We demonstrate that BFTs can directly cleave human epithelial-cadherin at extracellular domain 4, with BFT-2 possessing the highest activity. Using an alpaca antibody library, we identified a single-domain antibody, Nb2.43, targeting the BFTs. Nb2.43 can neutralize all three subtypes of BFT by directly binding the metalloenzyme catalytic zinc ion with its CDR3 antigen-binding loop. Furthermore, Nb2.43 blocks cleavage of E-cadherin by BFT and prevents the damage caused by ETBF in vitro and in a mouse colitis model. This work provides structural insights into BFT diversity and delivers a therapeutic nanobody against ETBF-mediated inflammation.
{"title":"Mechanistic diversity of Bacteroides fragilis toxins and neutralization with single domain antibody","authors":"Yucheng Guo , Zhenlin Ouyang , Wenbo He , Qian Qin , Jiaxin Zhang , Ting Yu , Min Jiao , Peter M. Hwang , Fang Zheng , Serge Muyldermans , Yurong Wen","doi":"10.1016/j.chembiol.2025.12.009","DOIUrl":"10.1016/j.chembiol.2025.12.009","url":null,"abstract":"<div><div>Enterotoxigenic <em>Bacteroides fragilis</em> (ETBF) promotes colonic inflammation by secreting metalloenzyme toxins (BFTs). Understanding BFT mechanisms and developing neutralization strategies is critical. Here, we have solved the structures of BFT-1 and BFT-2, revealing that residue 357 in the active site of the catalytic domain explains the diversity of function observed in BFT subtypes. We demonstrate that BFTs can directly cleave human epithelial-cadherin at extracellular domain 4, with BFT-2 possessing the highest activity. Using an alpaca antibody library, we identified a single-domain antibody, Nb2.43, targeting the BFTs. Nb2.43 can neutralize all three subtypes of BFT by directly binding the metalloenzyme catalytic zinc ion with its CDR3 antigen-binding loop. Furthermore, Nb2.43 blocks cleavage of E-cadherin by BFT and prevents the damage caused by ETBF <em>in vitro</em> and in a mouse colitis model. This work provides structural insights into BFT diversity and delivers a therapeutic nanobody against ETBF-mediated inflammation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 102-116.e6"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer’s disease) and alpha-synuclein in Parkinson’s disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.
{"title":"The interplay between autophagy and unconventional secretion in neurodegeneration","authors":"Maurizio Renna , Raffaella Bonavita , Grace Dixon , Luigi Vittorio Verdicchio , Angeleen Fleming","doi":"10.1016/j.chembiol.2025.12.007","DOIUrl":"10.1016/j.chembiol.2025.12.007","url":null,"abstract":"<div><div>Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer’s disease) and alpha-synuclein in Parkinson’s disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 10-32"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.005
Kirk W. Donovan , Eric Stefan , Bekim Bajrami , Melissa Bennion , Sarah Huff , Darsheed N. Mustafa , Mei-Ju Su , Sofya Dragan , Simone Sciabola , Yi-Ying Chou , Jude Prah , Xiaofeng Li , Douglas S. Johnson , Dominic M. Walsh , James S. Harvey
We report the discovery of a chemical series that enhances ApoE secretion from human astrocytes through mechanisms independent of LXR agonism. Target deconvolution of hits from a phenotypic screen in astrocytoma cells employed chemoproteomics, photoaffinity probes, in vitro KINOMEscan analysis, and targeted siRNA knockdown experiments. Photoaffinity labeling coupled with quantitative chemical proteomics identified aryl hydrocarbon receptor (AhR), a transcription factor not previously associated with ApoE secretion, as the primary target. A diverse panel of AhR agonists and antagonists together with genetic knockdown confirmed that ApoE secretion increases when AhR activity is reduced. Using a luciferase reporter assay, we demonstrated that active series analogs exhibit AhR antagonism while inactive compounds do not. Since deletion of AhR has severe peripheral effects, chronic inhibition of AhR is not an attractive therapeutic approach for Alzheimer’s disease; nevertheless, these results position AhR as a modulator of ApoE secretion and a biological pathway worth exploring.
{"title":"Identification of aryl hydrocarbon receptor as a functional target that enhances astrocytic ApoE secretion","authors":"Kirk W. Donovan , Eric Stefan , Bekim Bajrami , Melissa Bennion , Sarah Huff , Darsheed N. Mustafa , Mei-Ju Su , Sofya Dragan , Simone Sciabola , Yi-Ying Chou , Jude Prah , Xiaofeng Li , Douglas S. Johnson , Dominic M. Walsh , James S. Harvey","doi":"10.1016/j.chembiol.2025.12.005","DOIUrl":"10.1016/j.chembiol.2025.12.005","url":null,"abstract":"<div><div>We report the discovery of a chemical series that enhances ApoE secretion from human astrocytes through mechanisms independent of LXR agonism. Target deconvolution of hits from a phenotypic screen in astrocytoma cells employed chemoproteomics, photoaffinity probes, <em>in vitro</em> KINOMEscan analysis, and targeted siRNA knockdown experiments. Photoaffinity labeling coupled with quantitative chemical proteomics identified aryl hydrocarbon receptor (AhR), a transcription factor not previously associated with ApoE secretion, as the primary target. A diverse panel of AhR agonists and antagonists together with genetic knockdown confirmed that ApoE secretion increases when AhR activity is reduced. Using a luciferase reporter assay, we demonstrated that active series analogs exhibit AhR antagonism while inactive compounds do not. Since deletion of AhR has severe peripheral effects, chronic inhibition of AhR is not an attractive therapeutic approach for Alzheimer’s disease; nevertheless, these results position AhR as a modulator of ApoE secretion and a biological pathway worth exploring.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 91-101.e12"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.chembiol.2025.12.006
Yi-Ting Tsai , Nicolas-Frédéric Lipp , Olivia Seidel , Riya Varma , Aurelie Laguerre , Kristina Solorio-Kirpichyan , Adrian M. Wong , Roberto J. Brea , Grace H. McGregor , Thekla Cordes , Neal K. Devaraj , Lars Kuerschner , Sonya Neal , Christian M. Metallo , Itay Budin
1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, yet their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged sphingolipids. We observed that 1-deoxysphingolipids are retained in the endoplasmic reticulum (ER) and specifically in ER exit sites (ERESs), suggesting that they do not efficiently sort into vesicular carriers. Cell lines expressing disease-associated variants of serine palmitoyl-CoA transferase accumulated 1-deoxysphingolipids, which were accompanied by a reduction in ER membrane fluidity and enlargement of ERES. We found that the rates of membrane protein release from the ER were altered in response to 1-deoxysphingolipid metabolism in a manner dependent on the protein’s affinity for ordered or disordered membranes. The dysregulation of sphingolipid metabolism can thus alter secretory membrane properties and affect protein trafficking.
{"title":"1-deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway","authors":"Yi-Ting Tsai , Nicolas-Frédéric Lipp , Olivia Seidel , Riya Varma , Aurelie Laguerre , Kristina Solorio-Kirpichyan , Adrian M. Wong , Roberto J. Brea , Grace H. McGregor , Thekla Cordes , Neal K. Devaraj , Lars Kuerschner , Sonya Neal , Christian M. Metallo , Itay Budin","doi":"10.1016/j.chembiol.2025.12.006","DOIUrl":"10.1016/j.chembiol.2025.12.006","url":null,"abstract":"<div><div>1-Deoxysphingolipids are non-canonical sphingolipids linked to several diseases, yet their cellular effects are poorly understood. Here, we utilize lipid chemical biology approaches to investigate the role of 1-deoxysphingolipid metabolism on the properties and functions of secretory membranes. We applied organelle-specific bioorthogonal labeling to visualize the subcellular distribution of metabolically tagged sphingolipids. We observed that 1-deoxysphingolipids are retained in the endoplasmic reticulum (ER) and specifically in ER exit sites (ERESs), suggesting that they do not efficiently sort into vesicular carriers. Cell lines expressing disease-associated variants of serine palmitoyl-CoA transferase accumulated 1-deoxysphingolipids, which were accompanied by a reduction in ER membrane fluidity and enlargement of ERES. We found that the rates of membrane protein release from the ER were altered in response to 1-deoxysphingolipid metabolism in a manner dependent on the protein’s affinity for ordered or disordered membranes. The dysregulation of sphingolipid metabolism can thus alter secretory membrane properties and affect protein trafficking.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 1","pages":"Pages 45-58.e8"},"PeriodicalIF":7.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.chembiol.2025.12.010
Garrett L. Lindsey, Thomas K. Hockley, Alejandro Villa Gomez, Andrew C. Marshall, William R. Brothers, Colin T. Finney, Jacob Gross, Archa H. Fox, Gene W. Yeo, Bruno Melillo, Charles S. Bond, Benjamin F. Cravatt
{"title":"Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO","authors":"Garrett L. Lindsey, Thomas K. Hockley, Alejandro Villa Gomez, Andrew C. Marshall, William R. Brothers, Colin T. Finney, Jacob Gross, Archa H. Fox, Gene W. Yeo, Bruno Melillo, Charles S. Bond, Benjamin F. Cravatt","doi":"10.1016/j.chembiol.2025.12.010","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.12.010","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"21 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools—mostly the small-molecule kinase inhibitors—have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an “event-driven model” with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.
{"title":"Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities","authors":"Dong-Ting Ke, Zilong Zhan, Wenliang Zhang, Zhenyi Hu, Po-Han Chen","doi":"10.1016/j.chembiol.2025.12.012","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.12.012","url":null,"abstract":"Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools—mostly the small-molecule kinase inhibitors—have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an “event-driven model” with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"7 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Among the many proteins involved in cancer progression, an increasing number of RNA-binding proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases. In a recent study, small-molecule inhibitors have been identified as targeting NONO, an RBP known to be involved in mRNA splicing, DNA repair, and membraneless organelle stability. Here, we report the molecular basis of NONO targeting by the α-chloroacetamide molecule (R)-SKBG-1, its specific binding to NONO, and the enantiomer selectivity on the basis of mass spectrometry measurements and structure determination. We have determined the crystal structure of (R)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO. Altogether, these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer.
{"title":"Structural basis for NONO-specific modification by the α-chloroacetamide compound (R)-SKBG-1.","authors":"Alessia Vincenza Florio, Corinne Buré, Sébastien Fribourg","doi":"10.1016/j.chembiol.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.12.013","url":null,"abstract":"<p><p>Among the many proteins involved in cancer progression, an increasing number of RNA-binding proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases. In a recent study, small-molecule inhibitors have been identified as targeting NONO, an RBP known to be involved in mRNA splicing, DNA repair, and membraneless organelle stability. Here, we report the molecular basis of NONO targeting by the α-chloroacetamide molecule (R)-SKBG-1, its specific binding to NONO, and the enantiomer selectivity on the basis of mass spectrometry measurements and structure determination. We have determined the crystal structure of (R)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO. Altogether, these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":7.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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