Cell Chemical Biology最新文献_第4页

A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner 基于小脑的NEK7胶降解剂以上下文依赖的方式调节NLRP3炎性体

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.005

Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi

{"title":"A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner","authors":"Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi","doi":"10.1016/j.chembiol.2025.06.005","DOIUrl":"10.1016/j.chembiol.2025.06.005","url":null,"abstract":"<div><div>Aberrant NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective cereblon (CRBN) glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent interleukin-1β (IL-1β) release <em>in vitro</em> only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse <em>in vivo</em>. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 955-968.e13"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586803","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}

引用次数: 0

Silencing stress: Structural insights into ISR termination by the SIFI ubiquitin ligase 沉默压力：SIFI泛素连接酶对ISR终止的结构见解

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.007

Zeba Rizvi , Gabriel C. Lander

引用次数: 0

Plasmodium falciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity 一种具有抗疟活性的II型人激酶抑制剂可抑制恶性疟原虫蛋白激酶6和血色素的形成

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.003

Flore Nardella , Tiantian Jiang , Lushun Wang , Monica J. Bohmer , Subhoja Chakraborty , John Okombo , Jaeson Calla , Tatiane Macedo Silva , Samuel Pazicky , Jianwei Che , Jin Jeon , Evie Vincent , Nonlawat Boonyalai , Rachael Coyle , Mairi J. Buchanan , Samuel Schaefer , Daisy Chen , Amaan Khan , Emily Mayville , Mariana Laureano De Souza , Debopam Chakrabarti

{"title":"Plasmodium falciparum protein kinase 6 and hemozoin formation are inhibited by a type II human kinase inhibitor exhibiting antimalarial activity","authors":"Flore Nardella , Tiantian Jiang , Lushun Wang , Monica J. Bohmer , Subhoja Chakraborty , John Okombo , Jaeson Calla , Tatiane Macedo Silva , Samuel Pazicky , Jianwei Che , Jin Jeon , Evie Vincent , Nonlawat Boonyalai , Rachael Coyle , Mairi J. Buchanan , Samuel Schaefer , Daisy Chen , Amaan Khan , Emily Mayville , Mariana Laureano De Souza , Debopam Chakrabarti","doi":"10.1016/j.chembiol.2025.06.003","DOIUrl":"10.1016/j.chembiol.2025.06.003","url":null,"abstract":"<div><div>Kinase inhibitors are potent therapeutics, but most essential <em>Plasmodium</em> kinases remain unexploited as antimalarial targets. We identified compound <strong>12</strong>, a type II kinase inhibitor based on aminopyridine and 2,6-benzimidazole scaffolds, as a lead compound with nanomolar potency, fast action, and <em>in vivo</em> activity in the <em>Plasmodium berghei</em> rodent malaria model. Three-hybrid luciferase fragment complementation, enzymatic studies, and cellular thermal shift assays implicated <em>Plasmodium</em> protein kinase 6 (PfPK6) as the target. However, conditional knockdown of PfPK6 did not alter <strong>12</strong> potency, suggesting complex mechanisms of action. <em>In vitro</em> selection for compound <strong>12</strong> resistance revealed mutations in three transporters: multidrug-resistance protein 1, chloroquine resistance transporter and V-type ATPase, indicating a digestive vacuole site of action. Compound <strong>12</strong> inhibited β-hematin and hemozoin formation while increasing free heme levels, suggesting antimalarial activity via blockade of heme detoxification. Our studies repurpose a safe human kinase inhibitor as a potent, fast-acting antimalarial with established <em>in vivo</em> efficacy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 926-941.e23"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568957","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}

引用次数: 0

Covalent inhibition of ACSL4 alleviates ferroptosis-induced acute liver injury ACSL4共价抑制可减轻铁中毒引起的急性肝损伤

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-07-17 DOI: 10.1016/j.chembiol.2025.06.004

Maoyuan Linghu , Xianyu Luo , Xinru Zhou , Didi Liu , Qian Huang , Yi Ru , Yingli Luo , Yinchu Ma , Yi Huang

引用次数: 0

Flush with insight: Decoding GPCR crosstalk in the spinal defecation center 顿悟：解码脊髓排便中心的GPCR串音

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.011

Nil Casajuana-Martin , Eli F. McDonald , M. Madan Babu

引用次数: 0

Electrochemical sensor toolkit for simultaneous glutamate detection at edge of cleft and peri-soma 用于裂口边缘和体周谷氨酸同时检测的电化学传感器工具箱

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.002

Jie Liu , Yuandong Liu , Dongmin Yin , Yang Tian

{"title":"Electrochemical sensor toolkit for simultaneous glutamate detection at edge of cleft and peri-soma","authors":"Jie Liu , Yuandong Liu , Dongmin Yin , Yang Tian","doi":"10.1016/j.chembiol.2025.05.002","DOIUrl":"10.1016/j.chembiol.2025.05.002","url":null,"abstract":"<div><div>Simultaneously monitoring glutamate (Glu) dynamic at edge of synaptic cleft and peri-soma is crucial for understanding Glu-related pathology. Here, we created an electrochemical Glu sensors toolkit with spatial resolution of ∼60 nm, combining biologically engineered Glu binding protein for specifically capturing Glu together with chemically designed ferrocene groups for signal labeling. Modulation conjugation approach between GluR and ferrocene significantly improved sensitivity up to 32-folds. More importantly, protein engineering of residue mutation and linker peptides flexibility expanded linear range from 10 μM to 6 mM, accelerated on/off times down to 35/40 ms. This toolkit realized real-time quantifying of Glu both at edge of cleft and peri-soma, we discovered that Glu was almost released through SLC7A11 channels in calyx of held synapse upon oxygen-glucose-deprivation, while Glu was mainly released through hemichannels upon β-amyloid<sub>42</sub> stimulation. Our work provided a methodology for investigating Glu release and reuptake and offered insights for Glu related pathology.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 885-898.e11"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144202419","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}

引用次数: 0

Redundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation OST催化亚基的冗余有助于n -糖基化的治疗靶向

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.005

Marta Baro , Hojin Lee , Vanessa Kelley , Rongliang Lou , Chatchai Phoomak , Katerina Politi , Caroline J. Zeiss , Michael Van Zandt , Joseph N. Contessa

{"title":"Redundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation","authors":"Marta Baro , Hojin Lee , Vanessa Kelley , Rongliang Lou , Chatchai Phoomak , Katerina Politi , Caroline J. Zeiss , Michael Van Zandt , Joseph N. Contessa","doi":"10.1016/j.chembiol.2025.05.005","DOIUrl":"10.1016/j.chembiol.2025.05.005","url":null,"abstract":"<div><div>Protein asparagine (N)-glycosylation, which promotes the folding and trafficking of cell surface receptors, has not traditionally been viewed as a viable target in oncology due to the essential and non-redundant enzymatic activities required for glycan synthesis and transfer. However, in mammals, an exception is the presence of the oligosaccharyltransferase (OST) catalytic subunit paralogs, STT3A and STT3B. In this study, we investigate the biological activity of OST inhibitors and develop a strategy for selectively inhibiting N-glycosylation that is optimized for its downstream effects on the EGFR glycoprotein. Small molecules with improved pharmacokinetic properties and selective preferences for STT3A or STT3B were synthesized, characterized <em>in vitro</em>, and advanced to <em>in vivo</em> testing. The lead compound from this series, NGI-189, induces tumor regression or growth delay in patient-derived and TKI-resistant EGFR-mutant lung cancer xenografts without causing toxicity. Collectively, these findings suggest that bioavailable OST inhibitors can be developed as therapeutic agents for oncology.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 839-853.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237922","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}

引用次数: 0

EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses EGR2 o - glcn酰化调节原肿瘤巨噬细胞的发育，以限制CD8+ T细胞的抗肿瘤反应

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.007

Yuchen Zhang (章雨辰) , Hongpeng Li (李鸿鹏) , Yi Hao (郝熠) , Jiaqi Chen (陈家祺) , Xing Chen (陈兴) , Hang Yin (尹航)

{"title":"EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses","authors":"Yuchen Zhang (章雨辰) , Hongpeng Li (李鸿鹏) , Yi Hao (郝熠) , Jiaqi Chen (陈家祺) , Xing Chen (陈兴) , Hang Yin (尹航)","doi":"10.1016/j.chembiol.2025.05.007","DOIUrl":"10.1016/j.chembiol.2025.05.007","url":null,"abstract":"<div><div>Tumor associated macrophages (TAMs) exhibit a high capacity to take up glucose. However, how metabolic cues derived from glucose rewire TAMs remains unclear. Here, we report that glucose metabolism-driven protein O-GlcNAcylation increases in TAMs and shapes the differentiation and protumoral function of TAMs. Deficiency of O-GlcNAc transferase (OGT) in TAMs restricted tumor growth by reducing the proportion of C1QC<sup>+</sup> F4/80<sup>+</sup> TREM2<sup>+</sup> MerTK<sup>+</sup> TAMs as well as <em>Trem2 e</em>xpression, which in turn preserved the cytotoxic function of effector CD8<sup>+</sup> T cells while exhibiting reduced features of exhaustion. Mechanistically, O-GlcNAc targeted the macrophage-specific transcription factor EGR2 to promote its transcriptional activity. Transcriptional profiling revealed that OGT increased EGR2-related motifs accessibility in TAMs. O-GlcNAcylation of EGR2 at serine 299 enhanced its binding to myeloid cell differentiation-associated genes, including <em>Trem2</em>, thus facilitating the protumoral function of TAMs in GM-CSF-sufficient tumor. Overall, our work defines a tumor-specific reprogramming of protumoral TAMs via O-GlcNAc-modified EGR2 transcriptional regulation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 809-825.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252587","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}

引用次数: 0

Mechanism by which the molecular glue-like verteporfin induces IRE1α dimerization and activation to synergize with AKT inhibition in breast cancer 分子胶样维替波芬诱导乳腺癌中IRE1α二聚化和活化协同抑制AKT的机制

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.004

Yongliang Liu , Hui Hua , Yalan Cao , Minjing Li , Hongying Zhang , Shan Du , Jieya Liu , Ting Luo , Yangfu Jiang

{"title":"Mechanism by which the molecular glue-like verteporfin induces IRE1α dimerization and activation to synergize with AKT inhibition in breast cancer","authors":"Yongliang Liu , Hui Hua , Yalan Cao , Minjing Li , Hongying Zhang , Shan Du , Jieya Liu , Ting Luo , Yangfu Jiang","doi":"10.1016/j.chembiol.2025.05.004","DOIUrl":"10.1016/j.chembiol.2025.05.004","url":null,"abstract":"<div><div>Inositol-requiring enzyme 1α (IRE1α) signaling is one of three arms of the unfolded protein response, playing a vital role in maintaining endoplasmic reticulum homeostasis. Pharmacological modulation of this pathway offers potential therapeutic strategies for various diseases. Molecular glues may regulate protein stability and activity by inducing protein-protein interaction. Here, we find that verteporfin functions as a molecular glue, promoting IRE1α dimerization and activation. Specifically, verteporfin binds to IRE1α, facilitating its dimerization, which relies on the His692 residue. This activation of IRE1α triggers XBP1 splicing and miR-153-mediated downregulation of PTEN, along with AKT phosphorylation. Additionally, we identify the pro-metastasis gene <em>BACH1</em> as a novel target of miR-153, which is downregulated by IRE1α and verteporfin. While verteporfin inhibits breast cancer cell viability and invasion, its combination with an AKT inhibitor synergistically suppresses breast cancer progression. Our findings establish a mechanistic link between IRE1α and PI3K/AKT signaling, highlighting a possibility for therapeutic intervention.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 6","pages":"Pages 854-871.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144211168","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}

引用次数: 0

Two sides of a co(i)ndensate co(i)的两边紧密相连

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-06-19 DOI: 10.1016/j.chembiol.2025.05.010

Emre Pekbilir , Dorothee Dormann

引用次数: 0