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Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies 调控诱导接近靶向嵌合体--RIPTACs--用于癌症选择性疗法的异功能小分子策略
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.005
Kanak Raina , Chris D. Forbes , Rebecca Stronk , Jonathan P. Rappi Jr. , Kyle J. Eastman , Nilesh Zaware , Xinheng Yu , Hao Li , Amit Bhardwaj , Samuel W. Gerritz , Mia Forgione , Abigail Hundt , Madeline P. King , Zoe M. Posner , Allison D. Correia , Andrew McGovern , David E. Puleo , Rebekka Chenard , James J. Mousseau , J. Ignacio Vergara , Craig M. Crews
{"title":"Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies","authors":"Kanak Raina ,&nbsp;Chris D. Forbes ,&nbsp;Rebecca Stronk ,&nbsp;Jonathan P. Rappi Jr. ,&nbsp;Kyle J. Eastman ,&nbsp;Nilesh Zaware ,&nbsp;Xinheng Yu ,&nbsp;Hao Li ,&nbsp;Amit Bhardwaj ,&nbsp;Samuel W. Gerritz ,&nbsp;Mia Forgione ,&nbsp;Abigail Hundt ,&nbsp;Madeline P. King ,&nbsp;Zoe M. Posner ,&nbsp;Allison D. Correia ,&nbsp;Andrew McGovern ,&nbsp;David E. Puleo ,&nbsp;Rebekka Chenard ,&nbsp;James J. Mousseau ,&nbsp;J. Ignacio Vergara ,&nbsp;Craig M. Crews","doi":"10.1016/j.chembiol.2024.07.005","DOIUrl":"10.1016/j.chembiol.2024.07.005","url":null,"abstract":"<div><p>We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1490-1502.e42"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899985","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
AspSnFR: A genetically encoded biosensor for real-time monitoring of aspartate in live cells AspSnFR：用于实时监测活细胞中天冬氨酸的基因编码生物传感器
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.05.002
{"title":"AspSnFR: A genetically encoded biosensor for real-time monitoring of aspartate in live cells","authors":"","doi":"10.1016/j.chembiol.2024.05.002","DOIUrl":"10.1016/j.chembiol.2024.05.002","url":null,"abstract":"<div><p>Aspartate is crucial for nucleotide synthesis, ammonia detoxification, and maintaining redox balance via the malate-aspartate-shuttle (MAS). To disentangle these multiple roles of aspartate metabolism, tools are required that measure aspartate concentrations in real time and in live cells. We introduce AspSnFR, a genetically encoded green fluorescent biosensor for intracellular aspartate, engineered through displaying and screening biosensor libraries on mammalian cells. In live cells, AspSnFR is able to precisely and quantitatively measure cytosolic aspartate concentrations and dissect its production from glutamine. Combining high-content imaging of AspSnFR with pharmacological perturbations exposes differences in metabolic vulnerabilities of aspartate levels based on nutrient availability. Further, AspSnFR facilitates tracking of aspartate export from mitochondria through SLC25A12, the MAS’ key transporter. We show that SLC25A12 is a rapidly responding and direct route to couple Ca<sup>2+</sup> signaling with mitochondrial aspartate export. This establishes SLC25A12 as a crucial link between cellular signaling, mitochondrial respiration, and metabolism.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1529-1541.e12"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S245194562400179X/pdfft?md5=3b3153c35af18753feadccb80f236687&pid=1-s2.0-S245194562400179X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156564","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 chemistry of electrical signaling in sodium channels from bacteria and beyond 细菌等钠离子通道中的电信号化学反应
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.010
William A. Catterall , Tamer M. Gamal El-Din , Goragot Wisedchaisri
{"title":"The chemistry of electrical signaling in sodium channels from bacteria and beyond","authors":"William A. Catterall ,&nbsp;Tamer M. Gamal El-Din ,&nbsp;Goragot Wisedchaisri","doi":"10.1016/j.chembiol.2024.07.010","DOIUrl":"10.1016/j.chembiol.2024.07.010","url":null,"abstract":"<div><p>Electrical signaling is essential for all fast processes in biology, but its molecular mechanisms have been uncertain. This review article focuses on studies of bacterial sodium channels in order to home in on the essential molecular and chemical mechanisms underlying transmembrane ion conductance and voltage-dependent gating without the overlay of complex protein interactions and regulatory mechanisms in mammalian sodium channels. This minimalist approach has yielded a nearly complete picture of sodium channel function at the atomic level that are mostly conserved in mammalian sodium channels, including sodium selectivity and conductance, voltage sensing and activation, electromechanical coupling to pore opening and closing, slow inactivation, and pathogenic dysfunction in a debilitating channelopathy. Future studies of nature’s simplest sodium channels may continue to yield key insights into the fundamental molecular and chemical principles of their function and further elucidate the chemical basis of electrical signaling.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1405-1421"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S245194562400312X/pdfft?md5=0c34706ac158a70d52d3dd2d116ee049&pid=1-s2.0-S245194562400312X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990568","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
Meet the authors: Xueqin Jin, Jian Huang, Huan Wang, Kan Wang, and Nieng Yan 与作者见面金雪琴、黄健、王欢、王侃和严能
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.009
Xueqin Jin, Jian Huang, Huan Wang, Kan Wang, Nieng Yan
{"title":"Meet the authors: Xueqin Jin, Jian Huang, Huan Wang, Kan Wang, and Nieng Yan","authors":"Xueqin Jin,&nbsp;Jian Huang,&nbsp;Huan Wang,&nbsp;Kan Wang,&nbsp;Nieng Yan","doi":"10.1016/j.chembiol.2024.07.009","DOIUrl":"10.1016/j.chembiol.2024.07.009","url":null,"abstract":"<div><p>In an interview with Dr. Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the perspective entitled “A versatile residue numbering scheme for Na<sub>v</sub> and Ca<sub>v</sub> channels” share their thoughts on life as scientists.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1386-1387"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624003118/pdfft?md5=f053f546661ed81fd5923d1d16882438&pid=1-s2.0-S2451945624003118-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990629","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
Synthetic gene circuit evolution: Insights and opportunities at the mid-scale 合成基因回路进化：中等规模的洞察力和机遇
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.05.018
{"title":"Synthetic gene circuit evolution: Insights and opportunities at the mid-scale","authors":"","doi":"10.1016/j.chembiol.2024.05.018","DOIUrl":"10.1016/j.chembiol.2024.05.018","url":null,"abstract":"<div><p>Directed evolution focuses on optimizing single genetic components for predefined engineering goals by artificial mutagenesis and selection. In contrast, experimental evolution studies the adaptation of entire genomes in serially propagated cell populations, to provide an experimental basis for evolutionary theory. There is a relatively unexplored gap at the middle ground between these two techniques, to evolve <em>in vivo</em> entire synthetic gene circuits with nontrivial dynamic function instead of single parts or whole genomes. We discuss the requirements for such mid-scale evolution, with hypothetical examples for evolving synthetic gene circuits by appropriate selection and targeted shuffling of a seed set of genetic components <em>in vivo</em>. Implementing similar methods should aid the rapid generation, functionalization, and optimization of synthetic gene circuits in various organisms and environments, accelerating both the development of biomedical and technological applications and the understanding of principles guiding regulatory network evolution.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1447-1459"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624002198/pdfft?md5=ab725988d0ab4ed2c1198c5281ace930&pid=1-s2.0-S2451945624002198-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448798","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
Therapeutic potential of cis-targeting bispecific antibodies 顺式靶向双特异性抗体的治疗潜力
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.004
Rob C. Oslund , Pamela M. Holland , Scott A. Lesley , Olugbeminiyi O. Fadeyi
{"title":"Therapeutic potential of cis-targeting bispecific antibodies","authors":"Rob C. Oslund ,&nbsp;Pamela M. Holland ,&nbsp;Scott A. Lesley ,&nbsp;Olugbeminiyi O. Fadeyi","doi":"10.1016/j.chembiol.2024.07.004","DOIUrl":"10.1016/j.chembiol.2024.07.004","url":null,"abstract":"<div><p>The growing clinical success of bispecific antibodies (bsAbs) has led to rapid interest in leveraging dual targeting in order to generate novel modes of therapeutic action beyond mono-targeting approaches. While bsAbs that bind targets on two different cells (<em>trans</em>-targeting) are showing promise in the clinic, the co-targeting of two proteins on the same cell surface through <em>cis</em>-targeting bsAbs (<em>cis</em>-bsAbs) is an emerging strategy to elicit new functionalities. This includes the ability to induce proximity, enhance binding to a target, increase target/cell selectivity, and/or co-modulate function on the cell surface with the goal of altering, reversing, or eradicating abnormal cellular activity that contributes to disease. In this review, we focus on the impact of <em>cis</em>-bsAbs in the clinic, their emerging applications, and untangle the intricacies of improving bsAb discovery and development.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1473-1489"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895917","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
Carolyn Bertozzi: Building new bonds between molecules, fields, and communities 卡罗琳-贝托兹：在分子、领域和社区之间建立新的联系
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.015
Matthew R. Pratt , Jennifer A. Prescher
{"title":"Carolyn Bertozzi: Building new bonds between molecules, fields, and communities","authors":"Matthew R. Pratt ,&nbsp;Jennifer A. Prescher","doi":"10.1016/j.chembiol.2024.07.015","DOIUrl":"10.1016/j.chembiol.2024.07.015","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1383-1385"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624003179/pdfft?md5=4bf455a57cb56e81d734c6d2248d8ca7&pid=1-s2.0-S2451945624003179-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990628","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
Rescuing T cells from stiff tumors 从僵硬的肿瘤中拯救 T 细胞
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.011
Mario J. Avellaneda , Michael Sixt
{"title":"Rescuing T cells from stiff tumors","authors":"Mario J. Avellaneda ,&nbsp;Michael Sixt","doi":"10.1016/j.chembiol.2024.06.011","DOIUrl":"10.1016/j.chembiol.2024.06.011","url":null,"abstract":"<div><p>In a recent issue of <em>Cell</em>, Zhang et al.<span><span><sup>1</sup></span></span> demonstrate that mechanical features of a solid tumor can drive T cells into dysfunctionality and identify pathways that revert this “exhausted” state.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1242-1243"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636603","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
STX-bpc: “Brightening” the path to neuronal inhibition STX-bpc："照亮 "神经元抑制之路
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.008
Jinxia Wan , Yulong Li
{"title":"STX-bpc: “Brightening” the path to neuronal inhibition","authors":"Jinxia Wan ,&nbsp;Yulong Li","doi":"10.1016/j.chembiol.2024.06.008","DOIUrl":"10.1016/j.chembiol.2024.06.008","url":null,"abstract":"<div><p>In this issue of <em>Cell Chemical Biology</em>, Elleman et al.<span><span><sup>1</sup></span></span> introduce a transformative chemical approach to control neuronal activity with high spatial and temporal resolution. The authors present STX-bpc, a potent neurotoxin that naturally inhibits voltage-gated sodium channels (Na<sub>V</sub>s), complementing available optogenetic methods for manipulating neuronal activity, cellular communication, and behavior.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1233-1235"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636733","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
CBLs downregulation foretells T cell ubiquitination leading to autoimmunity CBLs 下调预示着 T 细胞泛素化会导致自身免疫病
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.010
Aurobind Vidyarthi , Joe Craft
{"title":"CBLs downregulation foretells T cell ubiquitination leading to autoimmunity","authors":"Aurobind Vidyarthi ,&nbsp;Joe Craft","doi":"10.1016/j.chembiol.2024.06.010","DOIUrl":"10.1016/j.chembiol.2024.06.010","url":null,"abstract":"<div><p>In a study published in the July issue of <em>Immunity</em>, Li et al.<span><span><sup>1</sup></span></span> demonstrate that expression of the E3 ubiquitin ligases CBL and CBL-B is downregulated in Tfh cells in SLE with Tfh cell expansion and autoimmunity. This leads to reduced ubiquitination of the T cell costimulator ICOS which regulates proteostasis of the Tfh cell transcription factor BCL6 via chaperone-mediated autophagy.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1239-1241"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636769","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
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