Cell Chemical Biology最新文献_第2页

CDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers CDK2异功能降解物共同降解CDK2和细胞周期蛋白E，从而对ccne1扩增和过表达的癌症有效

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-04-17 DOI: 10.1016/j.chembiol.2025.03.006

Nicholas Kwiatkowski , Tong Liang , Zhe Sha , Philip N. Collier , Annan Yang , Murugappan Sathappa , Atanu Paul , Lijing Su , Xiaozhang Zheng , Robert Aversa , Kunhua Li , Revonda Mehovic , Christina Kolodzy , Susanne B. Breitkopf , Dapeng Chen , Charles L. Howarth , Karen Yuan , Hakryul Jo , Joseph D. Growney , Matthew Weiss , Juliet Williams

{"title":"CDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers","authors":"Nicholas Kwiatkowski , Tong Liang , Zhe Sha , Philip N. Collier , Annan Yang , Murugappan Sathappa , Atanu Paul , Lijing Su , Xiaozhang Zheng , Robert Aversa , Kunhua Li , Revonda Mehovic , Christina Kolodzy , Susanne B. Breitkopf , Dapeng Chen , Charles L. Howarth , Karen Yuan , Hakryul Jo , Joseph D. Growney , Matthew Weiss , Juliet Williams","doi":"10.1016/j.chembiol.2025.03.006","DOIUrl":"10.1016/j.chembiol.2025.03.006","url":null,"abstract":"<div><div><em>CCNE1</em> amplification drives aberrant CDK2-cyclin E1 activity in cancer. Despite activity of CDK2 inhibitors, their therapeutic margins are limited by poor CDK selectivity. We developed a degrader with high selectivity for CDK2 over CDK1 that also unexpectedly led to cyclin E1 degradation and potent and complete suppression of RB phosphorylation at concentrations with low CDK2 occupancy and negligible CDK1 degradation. Co-depletion of CDK2 and cyclin E1 also resensitized palbociclib-adapted breast cancer cells to cell cycle blockade. Overall, the improved potency and selectivity of the degrader for CDK2 over small-molecule inhibitors drives antiproliferative activity with greater specificity for <em>CCNE1</em><sup><em>amp</em></sup> cancer cells and RB dependency. Using an orally administered degrader, we demonstrate deep and sustained RB pathway suppression, which is needed to induce stasis in <em>CCNE1</em><sup><em>amp</em></sup> tumors. These results highlight the potential of this modality to target CDK2 potently and selectivity in this biomarker-defined patient population with high unmet need.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 4","pages":"Pages 556-569.e24"},"PeriodicalIF":6.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838210","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

Molecular mechanism of PP2A/B55α phosphatase inhibition by IER5 IER5抑制PP2A/B55α磷酸酶的分子机制

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-04-17 DOI: 10.1016/j.chembiol.2025.03.004

Ruili Cao , Daniel T.D. Jones , Li Pan , Annie Yang , Shumei Wang , Sathish K.R. Padi , Shaun Rawson , Jon C. Aster , Stephen C. Blacklow

{"title":"Molecular mechanism of PP2A/B55α phosphatase inhibition by IER5","authors":"Ruili Cao , Daniel T.D. Jones , Li Pan , Annie Yang , Shumei Wang , Sathish K.R. Padi , Shaun Rawson , Jon C. Aster , Stephen C. Blacklow","doi":"10.1016/j.chembiol.2025.03.004","DOIUrl":"10.1016/j.chembiol.2025.03.004","url":null,"abstract":"<div><div>PP2A serine/threonine phosphatases are heterotrimeric complexes that execute many essential physiologic functions. These activities are modulated by additional regulatory proteins, such as ARPP19, FAM122A, and IER5. Here, we report the cryoelectron microscopy (cryo-EM) structure of a complex of PP2A/B55α with the N-terminal structured region of IER5 (IER5-N50), which occludes a surface on B55α used for substrate recruitment, and show that IER5-N50 inhibits PP2A/B55α catalyzed dephosphorylation of pTau in biochemical assays. Mutations of full-length IER5 that disrupt its PP2A/B55α interface interfere with co-immunoprecipitation of PP2A/B55α. IER5 antagonism of B55α in keratinocytes is required for expression of <em>KRT1</em>, a differentiation marker. Mini-IER5 composed of IER5-N50 and a nuclear localization sequence restores this activity in IER5 knockout cells. Using structural bioinformatics, we identify homology of IER5-N50 with SERTA (SEI-1, RBT-1, and TARA) domain containing proteins. These studies define the molecular basis of PP2A/B55α nuclear inhibition by IER5 and suggest a roadmap for selective pharmacologic modulation of PP2A/B55α complexes.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 4","pages":"Pages 631-642.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806304","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

Understanding, inhibiting, and engineering membrane transporters with high-throughput mutational screens 了解，抑制和工程膜转运与高通量突变筛选

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-04-17 DOI: 10.1016/j.chembiol.2025.03.003

Silas T. Miller , Christian B. Macdonald , Srivatsan Raman

{"title":"Understanding, inhibiting, and engineering membrane transporters with high-throughput mutational screens","authors":"Silas T. Miller , Christian B. Macdonald , Srivatsan Raman","doi":"10.1016/j.chembiol.2025.03.003","DOIUrl":"10.1016/j.chembiol.2025.03.003","url":null,"abstract":"<div><div>Promiscuous membrane transporters play vital roles across domains of life, mediating the uptake and efflux of structurally and chemically diverse substrates. Although many transporter structures have been solved, the fundamental rules of polyspecific transport remain inscrutable. In recent years, high-throughput genetic screens have solidified as powerful tools for comprehensive, unbiased measurements of variant function and hypothesis generation, but have had infrequent application and limited impact in the transporter field. In this primer, we describe the principles of high-throughput screening methods available for studying polyspecific transporters and comment on the necessity and potential of high-throughput methods for deciphering these transporters in particular. We present several screening approaches which could provide a fundamental understanding of the molecular basis of function and promiscuity in transporters. We further posit how this knowledge can be leveraged to design inhibitors that combat multidrug resistance and engineer transporters as needed tools for synthetic biology and biotechnology applications.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 4","pages":"Pages 529-541"},"PeriodicalIF":6.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736982","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

Visualization of calpain-1 activation during cell death and its role in GSDMD cleavage using chemical probes 利用化学探针观察细胞死亡过程中calpain-1的激活及其在GSDMD切割中的作用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-04-17 DOI: 10.1016/j.chembiol.2025.03.002

Natalia Horbach , Małgorzata Kalinka , Natalia Ćwilichowska-Puślecka , Abdulla Al Mamun , Agata Mikołajczyk-Martinez , Boris Turk , Scott J. Snipas , Paulina Kasperkiewicz , Katarzyna M. Groborz , Marcin Poręba

{"title":"Visualization of calpain-1 activation during cell death and its role in GSDMD cleavage using chemical probes","authors":"Natalia Horbach , Małgorzata Kalinka , Natalia Ćwilichowska-Puślecka , Abdulla Al Mamun , Agata Mikołajczyk-Martinez , Boris Turk , Scott J. Snipas , Paulina Kasperkiewicz , Katarzyna M. Groborz , Marcin Poręba","doi":"10.1016/j.chembiol.2025.03.002","DOIUrl":"10.1016/j.chembiol.2025.03.002","url":null,"abstract":"<div><div>Calpain-1, a calcium-dependent cysteine protease, plays a vital role in cellular processes such as cell death, cytoskeletal remodeling, signal transduction, and cell cycle progression. While its role in apoptosis, including substrate cleavage for orderly disassembly, is well established, its involvement in pyroptosis remains less understood. This study focused on developing chemical tools to detect calpain-1 activity. Using the hybrid combinatorial substrate library (HyCoSuL) approach with unnatural amino acids, we designed fluorescent substrates, inhibitors, and fluorescent activity-based probe (ABP) specific to calpain-1, enabling its visualization in living cells. We further investigated calpain-1’s expression alongside cell death proteins in immune cells using mass cytometry and observed strong colocalization with gasdermin D (GSDMD). Additionally, we demonstrated that calpain-1 can hydrolyze GSDMD <em>in vitro</em>. Through fluorescence-based substrate assays and mass spectrometry, we identified putative cleavage sites within the GSDMD sequence that may promote pyroptosis. These findings underscore calpain-1’s multifaceted role in cell death pathways, extending beyond apoptosis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 4","pages":"Pages 603-619.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723550","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

Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments 通过亲电片段的综合表型和活性分析发现抗生素靶标

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.001

Yizhen Jin , Sadhan Jana , Mikail E. Abbasov , Hening Lin

{"title":"Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments","authors":"Yizhen Jin , Sadhan Jana , Mikail E. Abbasov , Hening Lin","doi":"10.1016/j.chembiol.2025.02.001","DOIUrl":"10.1016/j.chembiol.2025.02.001","url":null,"abstract":"<div><div>The emergence of antibiotic resistance necessitates the discovery of novel bacterial targets and antimicrobial agents. Here, we present a bacterial target discovery framework that integrates phenotypic screening of cysteine-reactive fragments with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify β-ketoacyl-acyl carrier protein synthase III (FabH) and MiaA tRNA prenyltransferase as primary targets of a hit fragment, 10-F05, that confer bacterial stress resistance and virulence in <em>Shigella flexneri</em>. Mechanistic investigations elucidate that covalent C112 modification in FabH, an enzyme involved in bacterial fatty acid synthesis, results in its inactivation and consequent growth inhibition. We further demonstrate that irreversible C273 modification at the MiaA RNA-protein interaction interface abrogates substrate tRNA binding, attenuating resistance and virulence through decreased translational accuracy. Our findings underscore the efficacy of integrating phenotypic and activity-based profiling of electrophilic fragments to accelerate the identification and pharmacologic validation of new therapeutic targets.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 434-448.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507382","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

Epigenetic fluidity meets phenotypic malleability in intestinal epithelial cells 肠上皮细胞的表观遗传流动性符合表型可塑性

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.007

Swarnabh Bhattacharya , Ramesh A. Shivdasani

引用次数: 0

NAPE-PLD is target of thiazide diuretics NAPE-PLD是噻嗪类利尿剂的靶点

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.008

Sara Chiarugi , Francesco Margheriti , Valentina De Lorenzi , Elisa Martino , Eleonora Germana Margheritis , Aldo Moscardini , Roberto Marotta , Antonio Chaves-Sanjuan , Cristina Del Seppia , Giuseppe Federighi , Dominga Lapi , Tiziano Bandiera , Simona Rapposelli , Rossana Scuri , Martino Bolognesi , Gianpiero Garau

{"title":"NAPE-PLD is target of thiazide diuretics","authors":"Sara Chiarugi , Francesco Margheriti , Valentina De Lorenzi , Elisa Martino , Eleonora Germana Margheritis , Aldo Moscardini , Roberto Marotta , Antonio Chaves-Sanjuan , Cristina Del Seppia , Giuseppe Federighi , Dominga Lapi , Tiziano Bandiera , Simona Rapposelli , Rossana Scuri , Martino Bolognesi , Gianpiero Garau","doi":"10.1016/j.chembiol.2025.01.008","DOIUrl":"10.1016/j.chembiol.2025.01.008","url":null,"abstract":"<div><div>Thiazide and thiazide-like diuretics are among the most efficacious and used drugs for the treatment of hypertension, edema, and major cardiovascular outcomes. Despite more then than six decades of clinical use, the molecular target and mechanism of action by which these drugs cure hypertension after long-term use have remained mysterious. Here we report the discovery and validation of a previously unknown renal and extrarenal target of these antihypertensives, the membrane-associated phospholipase N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) of the endocannabinoid system. Structural and functional insights, together with preclinical studies in hypertensive rats, disclose the molecular and physiological basis by which thiazides cause acute diuresis and, at the same time, the distinctive chronic reduction of vascular resistance. Our results shed light on the mechanism of treatment of hypertension and will be useful for developing more efficacious medications for the management of vascular risk factors, as well as associated leukoencephalopathies and myelin disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 449-462.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477580","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

Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator fkbp12募集化学诱导邻近dna编码文库的建立及其在发现自噬增强剂中的应用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2024.12.002

Zher Yin Tan , Joel K.A. Adade , Xiebin Gu , Cody J.S. Hecht , Michael Salcius , Bingqi Tong , Shuang Liu , Seungmin Hwang , Frédéric J. Zécri , Daniel B. Graham , Stuart L. Schreiber , Ramnik J. Xavier

{"title":"Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator","authors":"Zher Yin Tan , Joel K.A. Adade , Xiebin Gu , Cody J.S. Hecht , Michael Salcius , Bingqi Tong , Shuang Liu , Seungmin Hwang , Frédéric J. Zécri , Daniel B. Graham , Stuart L. Schreiber , Ramnik J. Xavier","doi":"10.1016/j.chembiol.2024.12.002","DOIUrl":"10.1016/j.chembiol.2024.12.002","url":null,"abstract":"<div><div>Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate <em>ATG16L1</em> T300A, which confers genetic susceptibility to Crohn’s disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of <em>ATG16L1</em> T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 498-510.e35"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912189","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

An affinity-based depletion strategy for evaluating the effects of ergothioneine on bacterial physiology 麦角硫因对细菌生理影响的亲和耗尽评价策略

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.004

Anna B. Seminara , Stavroula K. Hatzios

{"title":"An affinity-based depletion strategy for evaluating the effects of ergothioneine on bacterial physiology","authors":"Anna B. Seminara , Stavroula K. Hatzios","doi":"10.1016/j.chembiol.2025.02.004","DOIUrl":"10.1016/j.chembiol.2025.02.004","url":null,"abstract":"<div><div>Ergothioneine (EGT) is a thiol-based antioxidant synthesized by certain fungal and bacterial species that is prevalent in the human diet. Recently, an EGT-specific transporter, EgtUV, was discovered in bacteria that are incapable of EGT biosynthesis, including the gastric pathogen <em>Helicobacter pylori</em>. However, EGT is naturally abundant in the complex media required to culture <em>H. pylori</em> and many other host-associated microbes, complicating efforts to understand how this molecule influences microbial physiology. Using the solute-binding domain of <em>H. pylori</em> EgtUV, we generated an EGT-chelating resin that depletes EGT from nutrient-rich media. We determined that wild-type <em>H. pylori</em> requires EGT to outcompete a transporter-deficient strain <em>in vitro</em>. Furthermore, EGT induces transcription of genes encoding outer-membrane transporters that may regulate intracellular EGT content upstream of the inner-membrane-localized EgtUV transporter. Our work establishes a method for tuning exposure to an abundant antioxidant <em>in vitro</em>, enabling future studies of EGT in diverse microbial strains and communities.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 486-497.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582511","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

Lipid it up: Freed fats drive ferroptosis 脂质化：释放的脂肪导致铁下垂

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.008

Madison S. Mortensen , Jennifer L. Watts

引用次数: 0