Cell Chemical Biology最新文献_第5页

Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation 靶向选择性PCK1和PGC-1α赖氨酸乙酰化的小分子通过增加乳酸氧化引起抗糖尿病作用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.005

Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, João Paulo G. Camporez, Shingo Kajimura, Gerald I. Shulman, Sheng Hui, Theodore M. Kamenecka, Patrick R. Griffin, Pere Puigserver

引用次数: 0

The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells 外排泵ABCC1/MRP1组成性地限制癌细胞中PROTAC的敏感性

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.11.009

Gernot Wolf , Conner Craigon , Shao Thing Teoh , Patrick Essletzbichler , Svenja Onstein , Diane Cassidy , Esther C.H. Uijttewaal , Vojtech Dvorak , Yuting Cao , Ariel Bensimon , Ulrich Elling , Alessio Ciulli , Giulio Superti-Furga

{"title":"The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells","authors":"Gernot Wolf , Conner Craigon , Shao Thing Teoh , Patrick Essletzbichler , Svenja Onstein , Diane Cassidy , Esther C.H. Uijttewaal , Vojtech Dvorak , Yuting Cao , Ariel Bensimon , Ulrich Elling , Alessio Ciulli , Giulio Superti-Furga","doi":"10.1016/j.chembiol.2024.11.009","DOIUrl":"10.1016/j.chembiol.2024.11.009","url":null,"abstract":"<div><div>Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for targeting “undruggable” proteins, and several PROTACs have reached the stage of clinical candidates. However, the roles of cellular transmembrane transporters in PROTAC uptake and efflux remain underexplored. Here, we utilized transporter-focused genetic screens to identify the ATP-binding cassette transporter ABCC1/MRP1 as a key PROTAC resistance factor. Unlike the previously identified inducible PROTAC exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers of various origins and constitutively restricts PROTAC bioavailability. Moreover, in a genome-wide PROTAC resistance screen, we identified candidates involved in processes such as ubiquitination, mTOR signaling, and apoptosis as genetic factors involved in PROTAC resistance. In summary, our findings reveal ABCC1 as a crucial constitutively active efflux pump limiting PROTAC efficacy in various cancer cells, offering insights for overcoming drug resistance.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 291-306.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Covalent targeting of splicing in T cells T 细胞剪接的共价靶向作用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.10.010

Kevin A. Scott , Hiroyuki Kojima , Nathalie Ropek , Charles D. Warren , Tiffany L. Zhang , Simon J. Hogg , Henry Sanford , Caroline Webster , Xiaoyu Zhang , Jahan Rahman , Bruno Melillo , Benjamin F. Cravatt , Jiankun Lyu , Omar Abdel-Wahab , Ekaterina V. Vinogradova

{"title":"Covalent targeting of splicing in T cells","authors":"Kevin A. Scott , Hiroyuki Kojima , Nathalie Ropek , Charles D. Warren , Tiffany L. Zhang , Simon J. Hogg , Henry Sanford , Caroline Webster , Xiaoyu Zhang , Jahan Rahman , Bruno Melillo , Benjamin F. Cravatt , Jiankun Lyu , Omar Abdel-Wahab , Ekaterina V. Vinogradova","doi":"10.1016/j.chembiol.2024.10.010","DOIUrl":"10.1016/j.chembiol.2024.10.010","url":null,"abstract":"<div><div>Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 201-218.e17"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696958","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

New opportunities in mechanistic and functional microbiome studies 机制和功能微生物组研究的新机遇

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.12.012

Judith Behnsen, Kerwyn Casey Huang, Matthew T. Sorbara, Meng C. Wang, Jun Yu, Melody Y. Zeng

引用次数: 0

Meet the authors: Katerina Jones, Camila Bernardo de Brito, and Mariana Xavier Byndloss 认识一下作者：卡特琳娜·琼斯、卡米拉·贝尔纳多·德·布里托和玛丽安娜·泽维尔·拜德罗斯

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.12.009

Katerina Jones, Camila Bernardo de Brito, Mariana Xavier Byndloss

引用次数: 0

Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway 人类 AKR1C3 与 GPR84 的激动剂结合，并参与扩展的多胺途径。

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.07.011

Natavan Dudkina , Hyun Bong Park , Deguang Song , Abhishek Jain , Sajid A. Khan , Richard A. Flavell , Caroline H. Johnson , Noah W. Palm , Jason M. Crawford

{"title":"Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway","authors":"Natavan Dudkina , Hyun Bong Park , Deguang Song , Abhishek Jain , Sajid A. Khan , Richard A. Flavell , Caroline H. Johnson , Noah W. Palm , Jason M. Crawford","doi":"10.1016/j.chembiol.2024.07.011","DOIUrl":"10.1016/j.chembiol.2024.07.011","url":null,"abstract":"<div><div>Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product “sperminal” is reduced to “sperminol.” Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy <em>in vitro</em>. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones <em>in vitro</em>, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 126-144.e18"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007975","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

The right tool for the job: Chemical biology and microbiome science 这项工作的正确工具：化学生物学和微生物组科学

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.12.004

Christopher Whidbey

引用次数: 0

Emerging biochemical, microbial and immunological evidence in the search for why HLA-B∗27 confers risk for spondyloarthritis 寻找 HLA-B∗27 为何会导致脊柱关节炎风险的生化、微生物和免疫学证据。

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.07.012

Eric M. Brown , Phuong N.U. Nguyen , Ramnik J. Xavier

{"title":"Emerging biochemical, microbial and immunological evidence in the search for why HLA-B∗27 confers risk for spondyloarthritis","authors":"Eric M. Brown , Phuong N.U. Nguyen , Ramnik J. Xavier","doi":"10.1016/j.chembiol.2024.07.012","DOIUrl":"10.1016/j.chembiol.2024.07.012","url":null,"abstract":"<div><div>The strong association of the human leukocyte antigen B<sup>∗</sup>27 alleles (<em>HLA-B<sup>∗</sup>27</em>) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B<sup>∗</sup>27 could trigger spondyloarthritis, with a focus on whether HLA-B<sup>∗</sup>27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B<sup>∗</sup>27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9<sup>+</sup> CD8<sup>+</sup> T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 12-24"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015826","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

Degradome analysis to identify direct protein substrates of small-molecule degraders 通过降解组分析确定小分子降解器的直接蛋白质底物

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.10.007

Marco Jochem , Anna Schrempf , Lina-Marie Wagner , Dmitri Segal , Jose Cisneros , Amanda Ng , Georg E. Winter , Jeroen Krijgsveld

{"title":"Degradome analysis to identify direct protein substrates of small-molecule degraders","authors":"Marco Jochem , Anna Schrempf , Lina-Marie Wagner , Dmitri Segal , Jose Cisneros , Amanda Ng , Georg E. Winter , Jeroen Krijgsveld","doi":"10.1016/j.chembiol.2024.10.007","DOIUrl":"10.1016/j.chembiol.2024.10.007","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) has emerged as a powerful strategy to selectively eliminate cellular proteins using small-molecule degraders, offering therapeutic promise for targeting proteins that are otherwise undruggable. However, a remaining challenge is to unambiguously identify primary TPD targets that are distinct from secondary downstream effects in the proteome. Here we introduce an approach for selective analysis of protein degradation by mass spectrometry (DegMS) at proteomic scale, which derives its specificity from the exclusion of confounding effects of altered transcription and translation induced by target depletion. We show that the approach efficiently operates at the timescale of TPD (hours) and we demonstrate its utility by analyzing the cyclin K degraders dCeMM2 and dCeMM4, which induce widespread transcriptional downregulation, and the GSPT1 degrader CC-885, an inhibitor of protein translation. Additionally, we apply DegMS to characterize a previously uncharacterized degrader, and identify the zinc-finger protein FIZ1 as a degraded target.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 192-200.e6"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden 基于酵母的口服疗法可提供免疫检查点抑制剂，减轻肠道肿瘤负担

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-01-16 DOI: 10.1016/j.chembiol.2024.10.013

Olivia N. Rebeck , Miranda J. Wallace , Jerome Prusa , Jie Ning , Esse M. Evbuomwan , Sunaina Rengarajan , LeMoyne Habimana-Griffin , Suryang Kwak , David Zahrah , Jason Tung , James Liao , Bejan Mahmud , Skye R.S. Fishbein , Erick S. Ramirez Tovar , Rehan Mehta , Bin Wang , Mark G. Gorelik , Beth A. Helmink , Gautam Dantas

{"title":"A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden","authors":"Olivia N. Rebeck , Miranda J. Wallace , Jerome Prusa , Jie Ning , Esse M. Evbuomwan , Sunaina Rengarajan , LeMoyne Habimana-Griffin , Suryang Kwak , David Zahrah , Jason Tung , James Liao , Bejan Mahmud , Skye R.S. Fishbein , Erick S. Ramirez Tovar , Rehan Mehta , Bin Wang , Mark G. Gorelik , Beth A. Helmink , Gautam Dantas","doi":"10.1016/j.chembiol.2024.10.013","DOIUrl":"10.1016/j.chembiol.2024.10.013","url":null,"abstract":"<div><div>Engineered probiotics are an emerging platform for <em>in situ</em> delivery of therapeutics to the gut. Herein, we developed an orally administered, yeast-based therapeutic delivery system to deliver next-generation immune checkpoint inhibitor (ICI) proteins directly to gastrointestinal tumors. We engineered <em>Saccharomyces cerevisiae</em> var. <em>boulardii</em> (<em>Sb</em>), a probiotic yeast with high genetic tractability and innate anticancer activity, to secrete “miniature” antibody variants that target programmed death ligand 1 (<em>Sb</em>_haPD-1). When tested in an ICI-refractory colorectal cancer (CRC) mouse model, <em>Sb</em>_haPD-1 significantly reduced intestinal tumor burden and resulted in significant shifts to the immune cell profile and microbiome composition. This oral therapeutic platform is modular and highly customizable, opening new avenues of targeted drug delivery that can be applied to treat a myriad of gastrointestinal malignancies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 1","pages":"Pages 98-110.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0