Cell Chemical Biology最新文献_第3页

A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer 一种高效的 LOX 双噻唑抑制剂可重构胶原结构并增强三阴性乳腺癌的化疗反应

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-21 DOI: 10.1016/j.chembiol.2024.06.012

Metin Cetin , Ozge Saatci , Abdol-Hossein Rezaeian , Chintada Nageswara Rao , Chad Beneker , Kukkamudi Sreenivas , Harrison Taylor , Breanna Pederson , Ioulia Chatzistamou , Brian Buckley , Susan Lessner , Peggi Angel , Campbell McInnes , Ozgur Sahin

{"title":"A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer","authors":"Metin Cetin , Ozge Saatci , Abdol-Hossein Rezaeian , Chintada Nageswara Rao , Chad Beneker , Kukkamudi Sreenivas , Harrison Taylor , Breanna Pederson , Ioulia Chatzistamou , Brian Buckley , Susan Lessner , Peggi Angel , Campbell McInnes , Ozgur Sahin","doi":"10.1016/j.chembiol.2024.06.012","DOIUrl":"10.1016/j.chembiol.2024.06.012","url":null,"abstract":"<div><div>Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and <em>in vivo</em>. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 1926-1941.e11"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746559","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

Bioluminescence assay of lysine deacylase sirtuin activity 赖氨酸脱乙酰酶 sirtuin 活性的生物发光测定

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-21 DOI: 10.1016/j.chembiol.2024.10.006

Alexandria N. Van Scoyk , Orlando Antelope , Donald E. Ayer , Randall T. Peterson , Anthony D. Pomicter , Shawn C. Owen , Michael W. Deininger

{"title":"Bioluminescence assay of lysine deacylase sirtuin activity","authors":"Alexandria N. Van Scoyk , Orlando Antelope , Donald E. Ayer , Randall T. Peterson , Anthony D. Pomicter , Shawn C. Owen , Michael W. Deininger","doi":"10.1016/j.chembiol.2024.10.006","DOIUrl":"10.1016/j.chembiol.2024.10.006","url":null,"abstract":"<div><div>Lysine acylation can direct protein function, localization, and interactions. Sirtuins deacylate lysine toward maintaining cellular homeostasis, and their aberrant expression contributes to the pathogenesis of multiple conditions, including cancer. Measuring sirtuins’ activity is essential to exploring their potential as therapeutic targets, but accurate quantification is challenging. We developed “SIRT<em>ify</em>”, a high-sensitivity assay for measuring sirtuin activity <em>in vitro</em> and <em>in vivo</em>. SIRT<em>ify</em> is based on a split-version of the NanoLuc luciferase consisting of a truncated, catalytically inactive N-terminal moiety (LgBiT) that complements with a high-affinity C-terminal peptide (p86) to form active luciferase. Acylation of two lysines within p86 disrupts binding to LgBiT and abates luminescence. Deacylation by sirtuins reestablishes p86 and restores binding, generating a luminescence signal proportional to sirtuin activity. Measurements accurately reflect reported sirtuin specificity for lysine-acylations and confirm the effects of sirtuin modulators. SIRT<em>ify</em> quantifies lysine deacylation dynamics and may be adaptable to monitoring additional post-translational modifications.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 11","pages":"Pages 2002-2014.e4"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594511","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

Decoding retrons: Breakthroughs in RT-DNA production and genome editing 解码 RT：RT-DNA 生产和基因组编辑方面的突破

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-21 DOI: 10.1016/j.chembiol.2024.10.011

Wenqian Liu , Yingjia Pan , Yu Zhang , Chang Dong , Lei Huang , Jiazhang Lian

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 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-20 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":"https://doi.org/10.1016/j.chembiol.2024.10.013","url":null,"abstract":"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.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"99 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-20","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Host specific sphingomyelin is critical for replication of diverse RNA viruses 宿主特异性鞘磷脂对多种 RNA 病毒的复制至关重要

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-19 DOI: 10.1016/j.chembiol.2024.10.009

Shuo Han, Xiaolei Ye, Jintong Yang, Xuefang Peng, Xiaming Jiang, Jin Li, Xiaojie Zheng, Xinchen Zhang, Yumin Zhang, Lingyu Zhang, Wei Wang, Jiaxin Li, Wenwen Xin, Xiaoai Zhang, Gengfu Xiao, Ke Peng, Leike Zhang, Xuguang Du, Lu Zhou, Wei Liu, Hao Li

{"title":"Host specific sphingomyelin is critical for replication of diverse RNA viruses","authors":"Shuo Han, Xiaolei Ye, Jintong Yang, Xuefang Peng, Xiaming Jiang, Jin Li, Xiaojie Zheng, Xinchen Zhang, Yumin Zhang, Lingyu Zhang, Wei Wang, Jiaxin Li, Wenwen Xin, Xiaoai Zhang, Gengfu Xiao, Ke Peng, Leike Zhang, Xuguang Du, Lu Zhou, Wei Liu, Hao Li","doi":"10.1016/j.chembiol.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.10.009","url":null,"abstract":"Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for infection by severe fever with thrombocytopenia syndrome virus (SFTSV). <em>SGMS1</em> knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in <em>SGMS1</em>-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum antiviral strategy.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"25 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670993","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

Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes 扩大可配体蛋白质组的化学工具：基于多样性合成的光活性立体配体

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-14 DOI: 10.1016/j.chembiol.2024.10.005

Daisuke Ogasawara, David B. Konrad, Zher Yin Tan, Kimberly L. Carey, Jessica Luo, Sang Joon Won, Haoxin Li, Trever R. Carter, Kristen E. DeMeester, Evert Njomen, Stuart L. Schreiber, Ramnik J. Xavier, Bruno Melillo, Benjamin F. Cravatt

{"title":"Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes","authors":"Daisuke Ogasawara, David B. Konrad, Zher Yin Tan, Kimberly L. Carey, Jessica Luo, Sang Joon Won, Haoxin Li, Trever R. Carter, Kristen E. DeMeester, Evert Njomen, Stuart L. Schreiber, Ramnik J. Xavier, Bruno Melillo, Benjamin F. Cravatt","doi":"10.1016/j.chembiol.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.10.005","url":null,"abstract":"Chemical proteomics enables the global analysis of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, remained limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these “photo-stereoprobes” interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible NanoBRET assays. Integrated phenotypic screening and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of DOS-inspired photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and facilitating the discovery and characterization of bioactive compounds in phenotypic screens.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"62 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610396","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

A PROTAC degrader suppresses oncogenic functions of PTK6 inducing apoptosis of breast cancer cells 一种 PROTAC 降解剂可抑制 PTK6 的致癌功能，诱导乳腺癌细胞凋亡

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-13 DOI: 10.1016/j.chembiol.2024.10.008

Criseyda Martinez, Yan Xiong, Alison Bartkowski, Ibuki Harada, Xiaoxiao Ren, Jessica Byerly, Elisa Port, Jian Jin, Hanna Irie

{"title":"A PROTAC degrader suppresses oncogenic functions of PTK6 inducing apoptosis of breast cancer cells","authors":"Criseyda Martinez, Yan Xiong, Alison Bartkowski, Ibuki Harada, Xiaoxiao Ren, Jessica Byerly, Elisa Port, Jian Jin, Hanna Irie","doi":"10.1016/j.chembiol.2024.10.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.10.008","url":null,"abstract":"Protein tyrosine kinase 6 (PTK6), a non-receptor tyrosine kinase, is an oncogenic driver in many tumor types. However, agents that therapeutically target PTK6 are lacking. Although several PTK6 kinase inhibitors have been developed, none have been clinically translated, which may be due to kinase-independent functions that compromise their efficacy. PTK6 kinase inhibitor treatment phenocopies some, but not all effects of PTK6 downregulation. PTK6 downregulation inhibits growth of breast cancer cells, but treatment with PTK6 kinase inhibitor does not. To chemically downregulate PTK6, we designed a PROTAC, MS105, which potently and specifically degrades PTK6. Treatment with MS105, but not PTK6 kinase inhibitor, inhibits growth and induces apoptosis of breast cancer cells, phenocopying the effects of PTK6 (short hairpin RNA) shRNA/CRISPR. In contrast, both MS105 and PTK6 kinase inhibitor effectively inhibit breast cancer cell migration, supporting the differing kinase dependencies of PTK6’s oncogenic functions. Our studies support PTK6 degraders as a preferred approach to targeting PTK6 in cancer.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"13 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601055","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 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-12 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":"https://doi.org/10.1016/j.chembiol.2024.10.007","url":null,"abstract":"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.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"71 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-11-12","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Next steps for targeted protein degradation 定向降解蛋白质的下一步行动

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-11-04 DOI: 10.1016/j.chembiol.2024.10.004

Mackenzie W. Krone, Craig M. Crews

引用次数: 0

Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis 鉴定两种以 GSDMD 寡聚界面 I 为靶点的再利用药物，以阻断焦细胞增多症

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2024-10-31 DOI: 10.1016/j.chembiol.2024.10.002

Yingchao Hu, Honghui Li, Xiangyu Zhang, Yuxian Song, Jun Liu, Jie Pu, Shuang Wen, Hongyang Xu, Hongliang Xin, Bingwei Wang, Shuo Yang

{"title":"Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis","authors":"Yingchao Hu, Honghui Li, Xiangyu Zhang, Yuxian Song, Jun Liu, Jie Pu, Shuang Wen, Hongyang Xu, Hongliang Xin, Bingwei Wang, Shuo Yang","doi":"10.1016/j.chembiol.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.10.002","url":null,"abstract":"As an executor of pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific “repurposed drugs” that potently suppress GSDMD-mediated pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of “1 + 1>2” in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"108 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556318","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