Cell Chemical Biology最新文献

Dynamic PRDX S-acylation modulates ROS stress and signaling

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-25 DOI: 10.1016/j.chembiol.2025.01.009

Tian Qiu, Saara-Anne Azizi, Shubhashree Pani, Bryan C. Dickinson

{"title":"Dynamic PRDX S-acylation modulates ROS stress and signaling","authors":"Tian Qiu, Saara-Anne Azizi, Shubhashree Pani, Bryan C. Dickinson","doi":"10.1016/j.chembiol.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.01.009","url":null,"abstract":"Peroxiredoxins (PRDXs) are a highly conserved family of peroxidases that serve as the primary scavengers of peroxides. Post-translational modifications play crucial roles modulating PRDX activities, tuning the balance between reactive oxygen species (ROS) signaling and stress. We previously reported that <em>S</em>-acylation occurs at the “peroxidatic” cysteine (Cp) site of PRDX5 and that it inhibits PRDX5 activity. Here, we show that the PRDX family more broadly is subject to <em>S</em>-acylation at the Cp site of all PRDXs and that PRDX <em>S</em>-acylation dynamically responds to cellular ROS levels. Using activity-based fluorescent imaging with DPP-Red, a red-shifted fluorescent indicator for acyl-protein thioesterase (APT) activity, we also discover that the instigation of ROS-stress via exogenous H<sub>2</sub>O<sub>2</sub> activates both the cytosolic and mitochondrial APTs, whereas epidermal growth factor (EGF)-stimulated endogenous H<sub>2</sub>O<sub>2</sub> deactivates the cytosolic APTs. These results indicate that APTs help tune H<sub>2</sub>O<sub>2</sub> signal transduction and ROS protection through PRDX <em>S</em>-deacylation.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"12 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486527","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

NAPE-PLD is target of thiazide diuretics

IF 8.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-24 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":"https://doi.org/10.1016/j.chembiol.2025.01.008","url":null,"abstract":"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.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"38 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2025-02-24","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

Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders 选择性极光激酶A降解物靶向神经母细胞瘤N-Myc

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.006

Jian Tang , Ramkumar Moorthy , Laura E. Hirsch , Özlem Demir , Zachary D. Baker , Jordan A. Naumann , Katherine F.M. Jones , Michael J. Grillo , Ella S. Haefner , Ke Shi , Michaella J. Levy , Harshita B. Gupta , Hideki Aihara , Reuben S. Harris , Rommie E. Amaro , Nicholas M. Levinson , Daniel A. Harki

{"title":"Targeting N-Myc in neuroblastoma with selective Aurora kinase A degraders","authors":"Jian Tang , Ramkumar Moorthy , Laura E. Hirsch , Özlem Demir , Zachary D. Baker , Jordan A. Naumann , Katherine F.M. Jones , Michael J. Grillo , Ella S. Haefner , Ke Shi , Michaella J. Levy , Harshita B. Gupta , Hideki Aihara , Reuben S. Harris , Rommie E. Amaro , Nicholas M. Levinson , Daniel A. Harki","doi":"10.1016/j.chembiol.2024.12.006","DOIUrl":"10.1016/j.chembiol.2024.12.006","url":null,"abstract":"<div><div>The N-Myc transcription factor, encoded by <em>MYCN</em>, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in <em>MYCN</em>-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels. A potent Aurora-A degrader, HLB-0532259 (compound <strong>4</strong>), was developed from an Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of Aurora-A, which elicits concomitant N-Myc degradation, with nanomolar potency and excellent selectivity. HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting “undruggable” proteins that are reliant on accessory proteins for cellular stabilization.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 352-362.e10"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935250","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

Dynamic sampling of a surveillance state enables DNA proofreading by Cas9 监控状态的动态取样使 Cas9 能够进行 DNA 校对

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.10.001

Viviane S. De Paula , Abhinav Dubey , Haribabu Arthanari , Nikolaos G. Sgourakis

{"title":"Dynamic sampling of a surveillance state enables DNA proofreading by Cas9","authors":"Viviane S. De Paula , Abhinav Dubey , Haribabu Arthanari , Nikolaos G. Sgourakis","doi":"10.1016/j.chembiol.2024.10.001","DOIUrl":"10.1016/j.chembiol.2024.10.001","url":null,"abstract":"<div><div>CRISPR-Cas9 has revolutionized genome engineering applications by programming its single-guide RNA, where high specificity is required. However, the precise molecular mechanism underscoring discrimination between on/off-target DNA sequences, relative to the guide RNA template, remains elusive. Here, using methyl-based NMR to study multiple holoenzymes assembled <em>in vitro</em>, we elucidate a discrete protein conformational state which enables recognition of DNA mismatches at the protospacer adjacent motif (PAM)-distal end. Our results delineate an allosteric pathway connecting a dynamic conformational switch at the REC3 domain, with the sampling of a catalytically competent state by the HNH domain. Our NMR data show that HiFi Cas9 (R691A) increases the fidelity of DNA recognition by stabilizing this \"surveillance state\" for mismatched substrates, shifting the Cas9 conformational equilibrium away from the active state. These results establish a paradigm of substrate recognition through an allosteric protein-based switch, providing unique insights into the molecular mechanism which governs Cas9 selectivity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 267-279.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519849","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

Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor 利用工程细菌外膜囊泡与转铁蛋白受体介导的溶酶体靶向嵌合体融合抗肿瘤免疫治疗

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.008

Ling-Yan Su, Yang Tian, Qiang Zheng, Yu Cao, Mengyu Yao, Shuangping Wang, Wen Xu, Chuyu Xi, Andrea Clocchiatti, Guangjun Nie, Hejiang Zhou

引用次数: 0

Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen 通过多路筛选发现铜绿假单胞菌外膜蛋白OprH-LPS相互作用的特异性小分子

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.001

Bradley E. Poulsen , Thulasi Warrier , Sulyman Barkho , Josephine Bagnall , Keith P. Romano , Tiantian White , Xiao Yu , Tomohiko Kawate , Phuong H. Nguyen , Kyra Raines , Kristina Ferrara , A. Lorelei Golas , Michael FitzGerald , Andras Boeszoermenyi , Virendar Kaushik , Michael Serrano-Wu , Noam Shoresh , Deborah T. Hung

{"title":"Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen","authors":"Bradley E. Poulsen , Thulasi Warrier , Sulyman Barkho , Josephine Bagnall , Keith P. Romano , Tiantian White , Xiao Yu , Tomohiko Kawate , Phuong H. Nguyen , Kyra Raines , Kristina Ferrara , A. Lorelei Golas , Michael FitzGerald , Andras Boeszoermenyi , Virendar Kaushik , Michael Serrano-Wu , Noam Shoresh , Deborah T. Hung","doi":"10.1016/j.chembiol.2024.12.001","DOIUrl":"10.1016/j.chembiol.2024.12.001","url":null,"abstract":"<div><div>The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against <em>Pseudomonas aeruginosa</em>, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of <em>P. aeruginosa</em> combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT, a target-based, whole-cell screening strategy, to discover small molecule probes that kill <em>P. aeruginosa</em> mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a <em>P. aeruginosa</em> mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal pathogen biology.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 307-324.e15"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888682","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 widespread and ancient bacterial machinery assembles cytochrome OmcS nanowires essential for extracellular electron transfer 一种广泛而古老的细菌机器组装细胞色素OmcS纳米线，对细胞外电子转移至关重要

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2024.12.013

Cong Shen , Aldo I. Salazar-Morales , Wonhyeuk Jung , Joey Erwin , Yangqi Gu , Anthony Coelho , Kallol Gupta , Sibel Ebru Yalcin , Fadel A. Samatey , Nikhil S. Malvankar

{"title":"A widespread and ancient bacterial machinery assembles cytochrome OmcS nanowires essential for extracellular electron transfer","authors":"Cong Shen , Aldo I. Salazar-Morales , Wonhyeuk Jung , Joey Erwin , Yangqi Gu , Anthony Coelho , Kallol Gupta , Sibel Ebru Yalcin , Fadel A. Samatey , Nikhil S. Malvankar","doi":"10.1016/j.chembiol.2024.12.013","DOIUrl":"10.1016/j.chembiol.2024.12.013","url":null,"abstract":"<div><div>Microbial extracellular electron transfer (EET) drives various globally important environmental phenomena and has biotechnology applications. Diverse prokaryotes have been proposed to perform EET via surface-displayed “nanowires” composed of multi-heme cytochromes. However, the mechanism that enables only a few cytochromes to polymerize into nanowires is unclear. Here, we identify a highly conserved <em><u>o</u>mc<u>S</u></em>-<u>c</u>ompanion (<em>osc</em>) cluster that drives the formation of cytochrome OmcS nanowires in <em>Geobacter sulfurreducens</em>. Through a combination of genetic, biochemical, and biophysical methods, we establish that prolyl isomerase-containing chaperon OscH, channel-like OscEFG, and β-propeller-like OscD are involved in the folding, secretion, and morphology maintenance of OmcS nanowires, respectively. OscH and OscG can interact with OmcS. Furthermore, overexpression of <em>oscG</em> accelerates EET by overproducing nanowires in an ATP-dependent manner. Heme loading splits OscD; Δ<em>oscD</em> accelerates cell growth, bundles nanowires into cables. Our findings establish the mechanism and prevalence of a specialized and modular assembly system for nanowires across phylogenetically diverse species and environments</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 239-254.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981366","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 genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.002

Joseph J. Smith , Taylor R. Valentino , Austin H. Ablicki , Riddhidev Banerjee , Adam R. Colligan , Debra M. Eckert , Gabrielle A. Desjardins , Katharine L. Diehl

{"title":"A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells","authors":"Joseph J. Smith , Taylor R. Valentino , Austin H. Ablicki , Riddhidev Banerjee , Adam R. Colligan , Debra M. Eckert , Gabrielle A. Desjardins , Katharine L. Diehl","doi":"10.1016/j.chembiol.2025.01.002","DOIUrl":"10.1016/j.chembiol.2025.01.002","url":null,"abstract":"<div><div>Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA metabolism is highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. Herein, we engineered an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). The sensor, “PancACe,” has a maximum change of ∼2-fold and a response range of ∼10 μM–2 mM acetyl-CoA. We demonstrated that the sensor has a greater than 7-fold selectivity over coenzyme A, butyryl-CoA, malonyl-CoA, and succinyl-CoA, and a 2.3-fold selectivity over propionyl-CoA. We expressed the sensor in <em>E. coli</em> and showed that it enables detection of rapid changes in acetyl-CoA levels. By localizing the sensor to either the cytoplasm, nucleus, or mitochondria in human cells, we showed that it enables subcellular detection of changes in acetyl-CoA levels, the magnitudes of which agreed with an orthogonal PicoProbe assay.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 325-337.e10"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044669","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

An oral tricyclic STING agonist suppresses tumor growth through remodeling of the immune microenvironment

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 DOI: 10.1016/j.chembiol.2025.01.004

Hong-Yi Zhao , Zhongwei Liu , Jinsong Tao , Shuai Mao , Meilin Wang , Miao He , Bo Wen , Wei Gao , Duxin Sun

{"title":"An oral tricyclic STING agonist suppresses tumor growth through remodeling of the immune microenvironment","authors":"Hong-Yi Zhao , Zhongwei Liu , Jinsong Tao , Shuai Mao , Meilin Wang , Miao He , Bo Wen , Wei Gao , Duxin Sun","doi":"10.1016/j.chembiol.2025.01.004","DOIUrl":"10.1016/j.chembiol.2025.01.004","url":null,"abstract":"<div><div>Stimulator of interferon genes (STING) agonists could overcome immunosuppressive microenvironment to improve cancer immunotherapy. However, it is challenging to develop oral STING agonists to achieve systemic immunity. In this study, we discovered ZSA-51 as a potent oral STING agonist with distinct benzo[4,5]thieno[2,3-<em>c</em>]pyrrole-1,3-dione scaffold through tricyclic scaffold screening. ZSA-51, as a prodrug, exhibited nanomolar <em>in vitro</em> STING activation activity and potent <em>in vivo</em> antitumor efficacy in both colon and pancreatic cancer models. The specificity of ZSA-51 in activating STING was confirmed using STING knockout cells and a structurally similar but negative control compound. Moreover, ZSA-51 demonstrated superior oral pharmacokinetic (PK) properties with low toxicity. Importantly, ZSA-51 remodeled immune microenvironment both in tumor and lymph node. Our data suggest that ZSA-51 is a potent oral STING agonist with robust anticancer efficacy, superior PK properties, and low toxicity, holding potential for future development for cancer immunotherapy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 280-290.e14"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077214","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 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 6.6 1区生物学

Cell Chemical Biology Pub Date : 2025-02-20 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":"10.1016/j.chembiol.2024.10.008","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 2","pages":"Pages 255-266.e8"},"PeriodicalIF":6.6,"publicationDate":"2025-02-20","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