Cell Chemical Biology最新文献_第10页

Dangerous liaisons: Promiscuous inhibition of CHK1 and AMPK is a lethal affair for cancer cells 危险的联系：CHK1和AMPK的混杂抑制是癌细胞的致命事件。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 DOI: 10.1016/j.chembiol.2026.05.011

Eudora L. Lu, Kevin Nay, John W. Scott

引用次数: 0

Covalent PPARγ inverse agonism by FX-909 reveals mechanistic insights into therapeutic targeting of PPARγ/RXRα-activated urothelial carcinoma FX-909的共价PPARγ拮抗作用揭示了PPARγ/ rxr α活化的尿路上皮癌靶向治疗的机制。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 Epub Date: 2026-05-28 DOI: 10.1016/j.chembiol.2026.04.017

Jacob I. Stuckey, Jennifer A. Mertz, Jonathan E. Wilson, Kaylyn E. Williamson, Yong Li, Miljan Kuljanin, Jeremy W. Setser, Byron DeLaBarre, Gregg Chenail, Phuong A. Nguyen, Mark E. Scott, Michael J. Geier, Christopher M. Bailey, William W. Motley, James E. Audia, Robert J. Sims III

{"title":"Covalent PPARγ inverse agonism by FX-909 reveals mechanistic insights into therapeutic targeting of PPARγ/RXRα-activated urothelial carcinoma","authors":"Jacob I. Stuckey, Jennifer A. Mertz, Jonathan E. Wilson, Kaylyn E. Williamson, Yong Li, Miljan Kuljanin, Jeremy W. Setser, Byron DeLaBarre, Gregg Chenail, Phuong A. Nguyen, Mark E. Scott, Michael J. Geier, Christopher M. Bailey, William W. Motley, James E. Audia, Robert J. Sims III","doi":"10.1016/j.chembiol.2026.04.017","DOIUrl":"10.1016/j.chembiol.2026.04.017","url":null,"abstract":"<div><div>We investigated the conformational mechanisms underlying PPARγ activation in muscle-invasive urothelial carcinoma (MIUC) and sought to develop covalent inverse agonists to therapeutically reinforce a repressive state. The integration of mutational, structural, and biochemical analyses of PPARγ and RXRα guided the discovery of FX-909, a first-in-class clinical PPARγ inverse agonist that enforces a repressive conformational state, even in highly activated biological contexts. FX-909 is a potent, highly selective, and powerful suppressor of PPARγ transcriptional activity through the enhancement of PPARγ-nuclear co-repressor (NCOR) binding affinity. Treatment with FX-909 resulted in selective growth inhibition in PPARγ-activated MIUC cell lines and durable regressions in xenograft models of MIUC. FX-909 is capable of recapitulating <em>PPARG</em> genetic knockout phenotypes <em>in vivo</em> and is currently in clinical development for the treatment of intractable MIUC.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 6","pages":"Pages 837-847.e14"},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051400","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

SpsB is a target of SOS-response inhibitor OXF-077 and regulates quinolone resistance emergence SpsB是sos反应抑制剂OXF-077的靶点，调控喹诺酮类药物耐药的出现。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 Epub Date: 2026-05-20 DOI: 10.1016/j.chembiol.2026.04.014

Jacob D. Bradbury, Timothy R. Walsh, Thomas Lanyon-Hogg

{"title":"SpsB is a target of SOS-response inhibitor OXF-077 and regulates quinolone resistance emergence","authors":"Jacob D. Bradbury, Timothy R. Walsh, Thomas Lanyon-Hogg","doi":"10.1016/j.chembiol.2026.04.014","DOIUrl":"10.1016/j.chembiol.2026.04.014","url":null,"abstract":"<div><div>Antimicrobial resistance (AMR) is a global health threat, urgently requiring novel compounds with new targets. One emerging strategy is the development of antibiotic adjuvants that inhibit the mutagenic SOS response in bacteria, thus prolonging antibiotic efficacy. <strong>OXF-077</strong> is a potent SOS-response inhibitor that suppresses the emergence of ciprofloxacin resistance in <em>Staphylococcus aureus</em>; however, the cellular target of <strong>OXF-077</strong> is unknown. We report here the use of affinity-based protein profiling to identify signal peptidase IB (SpsB) as a target of <strong>OXF-077</strong>. Genetic and chemical studies demonstrated that SpsB is required for the upregulation of the SOS response gene <em>recA</em> and increased frequency of resistance to ciprofloxacin. SpsB is therefore postulated to regulate the SOS response in <em>S. aureus,</em> representing a cell surface peptidase that can be targeted by small molecules to slow the evolution of resistance. Collectively, this work delivers SpsB as an attractive target to combat the urgent threat of AMR.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 6","pages":"Pages 877-885.e7"},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147985782","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

The cytotoxic effect of prexasertib is a consequence of dual inhibition on both CHK1 and AMPK prexasertib的细胞毒性作用是对CHK1和AMPK双重抑制的结果。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 Epub Date: 2026-04-29 DOI: 10.1016/j.chembiol.2026.04.003

Jing Guo, Ping Wang, Wei Liu, Xin Shi, Wei Wu, Xiaoyan Zhang, Qiang Chen

{"title":"The cytotoxic effect of prexasertib is a consequence of dual inhibition on both CHK1 and AMPK","authors":"Jing Guo, Ping Wang, Wei Liu, Xin Shi, Wei Wu, Xiaoyan Zhang, Qiang Chen","doi":"10.1016/j.chembiol.2026.04.003","DOIUrl":"10.1016/j.chembiol.2026.04.003","url":null,"abstract":"<div><div>Prexasertib (Prex) is a selective checkpoint kinase 1 and 2 (CHK1/2) inhibitor reported to induce the phosphorylation of AMP-activated protein kinase (AMPK) at threonine 172. However, the mechanism by which Prex regulates AMPK and whether this regulation contributes to Prex sensitivity is unknown. Here, we provide data that suggest that Prex directly binds to the cystathionine β-synthase (CBS) pockets of AMPK complex, leading to increased AMPKα Thr172 phosphorylation via CAMKK2 and LKB1. Intriguingly, Prex also functions as an ATP-competitive inhibitor of AMPK, and prolonged Prex treatment significantly inhibited AMPK <em>in vivo</em>. AMPK depletion enhanced cellular sensitivity to CHK1 inhibition, suggesting that Prex-induced cytotoxicity results from inhibition of CHK1 and AMPK. Exonuclease 1 (Exo1) hyperactivation following combined AMPK and CHK1 inhibition may represent a critical mechanism underlying Prex sensitivity. Our findings revealed an additional role of Prex in AMPK regulation and elucidated the functional significance of AMPK inhibition in CHK1 inhibitor-induced cell death.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 6","pages":"Pages 767-784.e7"},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809185","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

Giredestrant immobilizes the estrogen receptor to exert potent antitumor efficacy against ER-active breast cancers 固定化雌激素受体，对er活性乳腺癌发挥有效的抗肿瘤作用。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 Epub Date: 2026-05-19 DOI: 10.1016/j.chembiol.2026.04.008

Wei Zhou, Musaddeque Ahmed, Jane Guan, Natalie S. Fox, Jason Oeh, Ellen Ingalla, Amy Young, Lisa Tai, Jennifer Giltnane, Robert A. Blake, Jun Liang, Sharada S. Labadie, Vidhi Mody, Tom de Bruyn, Alejandro M. Chibly, Thao Nguyen, Xiaosai Yao, Xiaojing Wang, Marc Hafner, Ciara Metcalfe

{"title":"Giredestrant immobilizes the estrogen receptor to exert potent antitumor efficacy against ER-active breast cancers","authors":"Wei Zhou, Musaddeque Ahmed, Jane Guan, Natalie S. Fox, Jason Oeh, Ellen Ingalla, Amy Young, Lisa Tai, Jennifer Giltnane, Robert A. Blake, Jun Liang, Sharada S. Labadie, Vidhi Mody, Tom de Bruyn, Alejandro M. Chibly, Thao Nguyen, Xiaosai Yao, Xiaojing Wang, Marc Hafner, Ciara Metcalfe","doi":"10.1016/j.chembiol.2026.04.008","DOIUrl":"10.1016/j.chembiol.2026.04.008","url":null,"abstract":"<div><div>Estrogen receptor α (ER) is one of the most successfully prosecuted therapeutic targets in oncology. Selective ER degraders (SERDs) are being pursued as next-generation therapies. Giredestrant is a potent orally bioavailable SERD and full ER antagonist, which has demonstrated clinical superiority over standard-of-care therapy. Here, we describe its key pharmacological attributes, and account for its benefit across the ER+ breast cancer spectrum. The antiproliferative potential of giredestrant is dictated by ER activity; it outperforms approved agents in ER activity-high contexts. ER immobilization likely underlies giredestrant’s profound inhibitory potential. ER immobilization is not observed for heterobifunctional chimera degraders, which fail to match the antiproliferative potential of giredestrant despite superior ER degradation. Giredestrant redistributes enhancers, decreasing the expression of estrogen-induced genes and inducing the expression of putative tumor suppressors. These molecular data, together with results from recent trials, rationalize giredestrant’s potential to serve as an optimized endocrine backbone for ER+ breast cancer.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 6","pages":"Pages 785-798.e11"},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979738","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

S-acylation of TDP-43: PALMing down aggregation? TDP-43的s -酰化：掌向下聚集？

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 DOI: 10.1016/j.chembiol.2026.05.009

Ruonan Yang, Yanshan Fang

引用次数: 0

Optogenetic control of plasma membrane O-GlcNAcylation regulates WNK1 condensates and cellular signaling 光遗传学控制质膜o - glcn酰化调节WNK1凝聚物和细胞信号。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 Epub Date: 2026-06-02 DOI: 10.1016/j.chembiol.2026.05.002

Qiang Zhu , Qianyu Liu , Zhiya Fan , Yixiang Shi , Xinliang Liu , Yibo Guo , Jiancheng Luo , Jingguo Zhao , Weijie Qin , Yong Wang , Ping Wang , Haifeng Ye , Wen Yi

{"title":"Optogenetic control of plasma membrane O-GlcNAcylation regulates WNK1 condensates and cellular signaling","authors":"Qiang Zhu , Qianyu Liu , Zhiya Fan , Yixiang Shi , Xinliang Liu , Yibo Guo , Jiancheng Luo , Jingguo Zhao , Weijie Qin , Yong Wang , Ping Wang , Haifeng Ye , Wen Yi","doi":"10.1016/j.chembiol.2026.05.002","DOIUrl":"10.1016/j.chembiol.2026.05.002","url":null,"abstract":"<div><div>Glycosylation plays a pivotal role in regulating diverse biological processes. However, the lack of tools capable of controlling the spatiotemporal dynamics of glycosylation has largely hindered its functional elucidation. Here, we introduce an optogenetic approach that employs red/far-red light to dynamically and reversibly control the plasma membrane localization of O-linked N-acetylglucosamine transferase (OGT) in living systems. Red-light-induced translocation of OGT suppresses insulin signaling in both cells and mice. Glycoproteomic and phosphoproteomic analyses reveal a global impact of OGT-mediated glycosylation on signal transduction. Moreover, using protein semisynthesis, cell-based assays, and molecular dynamics simulations, we demonstrate that red-light-induced O-GlcNAcylation of WNK1 at S1949 inhibits downstream cell volume response signaling pathways by suppressing WNK1 biomolecular condensate formation. Together, our findings provide a valuable tool to modulate subcellular O-GlcNAcylation and control cellular signaling in living systems, with broad applicability to the study of glycosylation in cells.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 6","pages":"Pages 862-876.e8"},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148147845","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

Structure-based design of Sec61 translocon targeting prodrugs minimize off-target toxicity 基于结构的Sec61易位靶向前药设计最小化脱靶毒性。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 Epub Date: 2026-06-09 DOI: 10.1016/j.chembiol.2026.05.006

Qingqing Hao (郝青青) , Laurie Wang , Hui Pan (潘慧) , Xihui Xiao (萧锡辉) , Wenyan Dong (董文艳) , Wencong Pan (盘文聪) , Jingjing Sun (孙晶晶) , Wu Su (粟武) , Lijing Fang (房丽晶) , Eunyong Park , Guiyang Yao (姚贵阳)

{"title":"Structure-based design of Sec61 translocon targeting prodrugs minimize off-target toxicity","authors":"Qingqing Hao (郝青青) , Laurie Wang , Hui Pan (潘慧) , Xihui Xiao (萧锡辉) , Wenyan Dong (董文艳) , Wencong Pan (盘文聪) , Jingjing Sun (孙晶晶) , Wu Su (粟武) , Lijing Fang (房丽晶) , Eunyong Park , Guiyang Yao (姚贵阳)","doi":"10.1016/j.chembiol.2026.05.006","DOIUrl":"10.1016/j.chembiol.2026.05.006","url":null,"abstract":"<div><div>Coibamide A (CbA) is a cyclic depsipeptide that inhibits the function of the Sec61 translocon and exhibits significant antitumor activity. However, its broad Sec61 inhibition results in non-selective cytotoxicity, limiting therapeutic applications. To elucidate the molecular mechanism of CbA-mediated Sec61 blockade and enable rational prodrug design, we determined the cryo-EM structure of human Sec61 bound to CbA at 3.1 Å resolution. The structure reveals that CbA adopts a distinctive lasso-like conformation and occupies the lateral gate of Sec61, a binding site shared with other Sec61 inhibitors, while forming a particularly more expansive set of interactions with the lateral gate. Guided by these structural insights, we conducted structure-activity relationship studies and developed prodrug strategies that modulate CbA’s antitumor activity through the controlled perturbation of intramolecular and protein hydrogen bonding interactions. Together, these results establish a structure-guided strategy for prodrug design of CbA and demonstrate the general applicability of backbone-caging to enhance the tolerability of Sec61 inhibitors.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 6","pages":"Pages 823-836.e21"},"PeriodicalIF":9.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209325","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

Intercepting the SOS message: SpsB inhibition by OXF-077 stalls the evolution of antibiotic resistance 拦截SOS信息：OXF-077抑制SpsB延缓抗生素耐药性的进化。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 DOI: 10.1016/j.chembiol.2026.05.010

Marina Murillo-Torres, Sara Diaz-Diaz, José Manuel Rodríguez-Martínez

引用次数: 0

Extrabody: An optogenetic remote for extracellular antigen-driven cell behaviors 体外：细胞外抗原驱动细胞行为的光遗传学遥控器。

IF 9 1区生物学

Cell Chemical Biology Pub Date : 2026-06-18 DOI: 10.1016/j.chembiol.2026.05.018

Zhenghua Wang, Yulong Li

引用次数: 0