Pub Date : 2025-10-16DOI: 10.1016/j.chembiol.2025.09.010
Timothy N. Perkins
The receptor for advanced glycation end products (RAGE) drives inflammation in several chronic diseases. In this issue of Cell Chemical Biology, Theophall et al.1 built a structural model of the actin polymerase-inducing RAGE-Diaphanous 1 complex and identified a small molecule that disrupts this interaction, enhancing wound healing and reducing inflammation in vivo.
{"title":"Disrupting intracellular RAGE signaling to combat pathological inflammation in disease","authors":"Timothy N. Perkins","doi":"10.1016/j.chembiol.2025.09.010","DOIUrl":"10.1016/j.chembiol.2025.09.010","url":null,"abstract":"<div><div>The receptor for advanced glycation end products (RAGE) drives inflammation in several chronic diseases. In this issue of <em>Cell Chemical Biology</em>, Theophall et al.<span><span><sup>1</sup></span></span> built a structural model of the actin polymerase-inducing RAGE-Diaphanous 1 complex and identified a small molecule that disrupts this interaction, enhancing wound healing and reducing inflammation <em>in vivo</em>.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 10","pages":"Pages 1197-1199"},"PeriodicalIF":7.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295275","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}
Basal-like breast cancer is an aggressive subtype with limited therapeutic options. Here, transcriptomic analysis of public datasets suggested distinct subtype- and cell-specific expression patterns of ALDH1A isoforms in breast tumors, with ALDH1A3 predominantly expressed in the epithelial cells of basal-like tumors, whereas ALDH1A2 and ALDH1A1 were enriched in stromal and immune-associated subpopulations. High expression of ALDH1A3 and ALDH1A2, but not ALDH1A1, is associated with poor prognosis in high-grade, lymph-node-positive tumors. To evaluate therapeutic targeting, we developed ABD0171, an irreversible, selective ALDH1A3 inhibitor with additional ALDH1A1 activity. ABD0171 disrupted key oncogenic pathways, including IL6/JAK/STAT3, tPA, and Src/FAK, resulting in robust antitumor and antimetastatic effects in vitro and in vivo, with a favorable safety profile. These findings establish ALDH1A3 as a therapeutic target in breast cancers with epithelial-basal traits and validate ABD0171 as a promising clinical candidate to address current treatment challenges.
{"title":"Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors","authors":"Raquel Pequerul , Andrada Constantinescu , Bassam Janji , Akinchan Kumar , Céline Baier , Iris Manosalva , Xavier Parés , Oscar Palacios , Salvatore Spicuglia , Delphine Colignon , Axelle Berrou , Guy Fournet , Paul Berchard , Guillaume Martin , Ismail Ceylan , Rocio Rebollido-Rios , Jaume Farrés , Mileidys Perez-Alea","doi":"10.1016/j.chembiol.2025.09.003","DOIUrl":"10.1016/j.chembiol.2025.09.003","url":null,"abstract":"<div><div>Basal-like breast cancer is an aggressive subtype with limited therapeutic options. Here, transcriptomic analysis of public datasets suggested distinct subtype- and cell-specific expression patterns of ALDH1A isoforms in breast tumors, with <em>ALDH1A3</em> predominantly expressed in the epithelial cells of basal-like tumors, whereas <em>ALDH1A2</em> and <em>ALDH1A1</em> were enriched in stromal and immune-associated subpopulations. High expression of <em>ALDH1A3</em> and <em>ALDH1A2</em>, but not <em>ALDH1A1</em>, is associated with poor prognosis in high-grade, lymph-node-positive tumors. To evaluate therapeutic targeting, we developed ABD0171, an irreversible, selective ALDH1A3 inhibitor with additional ALDH1A1 activity. ABD0171 disrupted key oncogenic pathways, including IL6/JAK/STAT3, tPA, and Src/FAK, resulting in robust antitumor and antimetastatic effects <em>in vitro</em> and <em>in vivo</em>, with a favorable safety profile. These findings establish ALDH1A3 as a therapeutic target in breast cancers with epithelial-basal traits and validate ABD0171 as a promising clinical candidate to address current treatment challenges.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 10","pages":"Pages 1260-1278.e12"},"PeriodicalIF":7.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189340","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}
Pub Date : 2025-10-16DOI: 10.1016/j.chembiol.2025.09.005
Huiti Li , Ying Xu , Yimin Zheng , Zian Xue , Qingqing Li , Xinglong Jia , Lietao Weng , Lulu Jiang , Xiaoxue Ruan , Rong Zhang , Yue Yin , Liying Zhou , Fuyuan Li , He Huang , Jin Li , Minjia Tan , Jia Fan , Jiabin Cai , Guoqiang Chen , Lu Zhou
HIF-1α transcriptional activity is enhanced through SUMOylation mediated by CBX4. Despite the recognized importance of the CBX4-HIF-1α axis, the molecular mechanisms governing its regulation remain largely unclear. In this study, phenotypic screening of a 101,254-compound library followed by structural optimization led to the identification of XZA-1, a small molecule capable of disrupting CBX4-mediated HIF-1α transcriptional activation. Mechanistic investigations revealed that XZA-1 activates HADH, a key enzyme in fatty acid β-oxidation, resulting in increased intracellular levels of acetoacetyl-CoA. This metabolite promotes acetoacetylation of CBX4 at lysine 106, thereby reducing its SUMO E3 ligase activity. In a CBX4-overexpressing xenograft model, XZA-1 demonstrated antitumor effects by enhancing CBX4 K106 acetoacetylation. Additionally, elevated levels of CBX4 K106 acetoacetylation were observed in clinical HCC tissues from patients with better overall survival. These findings suggest that acetoacetyl-CoA functions as a potential antitumor metabolite and establish a novel pharmacological approach for modulating HIF-1α transcriptional activity in cancer.
{"title":"CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity","authors":"Huiti Li , Ying Xu , Yimin Zheng , Zian Xue , Qingqing Li , Xinglong Jia , Lietao Weng , Lulu Jiang , Xiaoxue Ruan , Rong Zhang , Yue Yin , Liying Zhou , Fuyuan Li , He Huang , Jin Li , Minjia Tan , Jia Fan , Jiabin Cai , Guoqiang Chen , Lu Zhou","doi":"10.1016/j.chembiol.2025.09.005","DOIUrl":"10.1016/j.chembiol.2025.09.005","url":null,"abstract":"<div><div>HIF-1α transcriptional activity is enhanced through SUMOylation mediated by CBX4. Despite the recognized importance of the CBX4-HIF-1α axis, the molecular mechanisms governing its regulation remain largely unclear. In this study, phenotypic screening of a 101,254-compound library followed by structural optimization led to the identification of <strong>XZA-1</strong>, a small molecule capable of disrupting CBX4-mediated HIF-1α transcriptional activation. Mechanistic investigations revealed that <strong>XZA-1</strong> activates HADH, a key enzyme in fatty acid β-oxidation, resulting in increased intracellular levels of acetoacetyl-CoA. This metabolite promotes acetoacetylation of CBX4 at lysine 106, thereby reducing its SUMO E3 ligase activity. In a CBX4-overexpressing xenograft model, <strong>XZA-1</strong> demonstrated antitumor effects by enhancing CBX4 K106 acetoacetylation. Additionally, elevated levels of CBX4 K106 acetoacetylation were observed in clinical HCC tissues from patients with better overall survival. These findings suggest that acetoacetyl-CoA functions as a potential antitumor metabolite and establish a novel pharmacological approach for modulating HIF-1α transcriptional activity in cancer.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 10","pages":"Pages 1249-1259.e9"},"PeriodicalIF":7.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209455","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}
Pub Date : 2025-10-16DOI: 10.1016/j.chembiol.2025.09.001
Alva G. Sainz , Furkan E. Oflaz , Xinnan Wang
The prevailing theory on the origins of mitochondria proposes that they were once independent organisms. Though symbiotically integrated into eukaryotic cells, they have retained a striking degree of autonomy. This self-governance manifests as the capacity to sense internal metabolic, ionic, and redox states and transduce these into signals that modulate cellular function—a process we refer to as mitochondrial inside-out signaling. These mitochondria-initiated signaling mechanisms are crucial for bioenergetic homeostasis of all cells, including neurons. Unlike conventional outside-in signaling, these mitochondria-initiated signals stem from within the organelle and propagate outward, tuning cytosolic signaling pathways, nuclear transcriptional programs, and neuronal behavior. In this review, we provide mechanistic insights into this distinct and underappreciated signaling modality, discussing how internal mitochondrial conditions are sensed and transmitted to the cytosol and how these signaling events influence mitochondrial and cellular health with a focus on their implications for neuronal physiology and disease vulnerability.
{"title":"Sensing within: Mitochondrial inside-out signal transduction","authors":"Alva G. Sainz , Furkan E. Oflaz , Xinnan Wang","doi":"10.1016/j.chembiol.2025.09.001","DOIUrl":"10.1016/j.chembiol.2025.09.001","url":null,"abstract":"<div><div>The prevailing theory on the origins of mitochondria proposes that they were once independent organisms. Though symbiotically integrated into eukaryotic cells, they have retained a striking degree of autonomy. This self-governance manifests as the capacity to sense internal metabolic, ionic, and redox states and transduce these into signals that modulate cellular function—a process we refer to as <em>mitochondrial inside-out signaling.</em> These mitochondria-initiated signaling mechanisms are crucial for bioenergetic homeostasis of all cells, including neurons. Unlike conventional outside-in signaling, these mitochondria-initiated signals stem from within the organelle and propagate outward, tuning cytosolic signaling pathways, nuclear transcriptional programs, and neuronal behavior. In this review, we provide mechanistic insights into this distinct and underappreciated signaling modality, discussing how internal mitochondrial conditions are sensed and transmitted to the cytosol and how these signaling events influence mitochondrial and cellular health with a focus on their implications for neuronal physiology and disease vulnerability.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 10","pages":"Pages 1205-1220"},"PeriodicalIF":7.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134469","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}
Pub Date : 2025-10-16DOI: 10.1016/j.chembiol.2025.09.008
Boran Li , Qiming Sun
Organellophagy receptors have been reported previously, but the underlying mechanisms of their function remain unclear. In a recent issue of Nature Cell Biology, Rudinskiy et al. demonstrated that the intrinsically disordered regions (IDRs) of the receptors function as interchangeable modular codes, driving organelle fragmentation. This provides insights for the exploration of future models of organellophagy receptor function.
{"title":"Organelle-ly speaking: Cracking the code of cellular clean-up","authors":"Boran Li , Qiming Sun","doi":"10.1016/j.chembiol.2025.09.008","DOIUrl":"10.1016/j.chembiol.2025.09.008","url":null,"abstract":"<div><div>Organellophagy receptors have been reported previously, but the underlying mechanisms of their function remain unclear. In a recent issue of <em>Nature Cell Biology</em>, Rudinskiy et al. demonstrated that the intrinsically disordered regions (IDRs) of the receptors function as interchangeable modular codes, driving organelle fragmentation. This provides insights for the exploration of future models of organellophagy receptor function.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 10","pages":"Pages 1202-1204"},"PeriodicalIF":7.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295281","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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.001
Raffaella De Pace , Saikat Ghosh , Chad D. Williamson , Juan S. Bonifacino
Endolysosomes are dynamic organelles that undergo movement along the cytoskeleton, fusion, fission, and tubulation during their lifetime. These processes are regulated by complex molecular machineries, including the structurally related hetero-octameric complexes BLOC-1 and BORC. BLOC-1 associates with early endosomes to mediate the biogenesis of lysosome-related organelles (LROs), such as melanosomes and platelet dense bodies. Accordingly, mutations in BLOC-1 subunits cause Hermansky-Pudlak syndrome (HPS), a disorder characterized by pigmentation defects and bleeding abnormalities. In contrast, BORC associates with lysosomes, late endosomes, and synaptic vesicle precursors, promoting their transport along microtubules. BORC also regulates endolysosome fusion with other endolysosomes, as well as with phagosomes and autophagosomes. Mutations in BORC subunits cause a severe neurodevelopmental disorder in humans. In this article, we review recent progress in the elucidation of the structure, evolution, physiological roles, and regulation of BLOC-1 and BORC, highlighting their critical contributions to maintaining endolysosomal organization and function.
{"title":"BLOC-1 and BORC: Complex regulators of endolysosomal dynamics","authors":"Raffaella De Pace , Saikat Ghosh , Chad D. Williamson , Juan S. Bonifacino","doi":"10.1016/j.chembiol.2025.08.001","DOIUrl":"10.1016/j.chembiol.2025.08.001","url":null,"abstract":"<div><div>Endolysosomes are dynamic organelles that undergo movement along the cytoskeleton, fusion, fission, and tubulation during their lifetime. These processes are regulated by complex molecular machineries, including the structurally related hetero-octameric complexes BLOC-1 and BORC. BLOC-1 associates with early endosomes to mediate the biogenesis of lysosome-related organelles (LROs), such as melanosomes and platelet dense bodies. Accordingly, mutations in BLOC-1 subunits cause Hermansky-Pudlak syndrome (HPS), a disorder characterized by pigmentation defects and bleeding abnormalities. In contrast, BORC associates with lysosomes, late endosomes, and synaptic vesicle precursors, promoting their transport along microtubules. BORC also regulates endolysosome fusion with other endolysosomes, as well as with phagosomes and autophagosomes. Mutations in BORC subunits cause a severe neurodevelopmental disorder in humans. In this article, we review recent progress in the elucidation of the structure, evolution, physiological roles, and regulation of BLOC-1 and BORC, highlighting their critical contributions to maintaining endolysosomal organization and function.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1106-1124"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901103","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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.002
Ariana S. Bratt , Susan Kilgas , Maria I. Tarazona Guzman , Robert S. Magin , Isabella Jaen Maisonet , Cara A. Starnbach , Wei Pin Teh , Anthony C. Varca , Bin Hu , Esteban Tarazona Guzman , Hyuk-Soo Seo , Sirano Dhe-Paganon , Nicholas M. Girardi , Guillaume Adelmant , Jarrod A. Marto , Dipanjan Chowdhury , Sara J. Buhrlage
Deubiquitinating enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed CAS-010, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor. We validated on-target effects of CAS-010 on the negative regulation of p53 transactivation in the wild-type setting. We demonstrated that CAS-010 disrupts the 53BP1-USP28 interaction, and more broadly showed that USP28 catalytic activity contributes to this key interaction. Taken together, CAS-010 and the accompanying negative control compound WPT-086 and inhibitor-resistant mutant provide well-validated tools for further characterizing the role of USP28 in p53-mediated effect on cell cycle control and cell fate.
{"title":"Pharmacologic interrogation of USP28 cellular function in p53 signaling","authors":"Ariana S. Bratt , Susan Kilgas , Maria I. Tarazona Guzman , Robert S. Magin , Isabella Jaen Maisonet , Cara A. Starnbach , Wei Pin Teh , Anthony C. Varca , Bin Hu , Esteban Tarazona Guzman , Hyuk-Soo Seo , Sirano Dhe-Paganon , Nicholas M. Girardi , Guillaume Adelmant , Jarrod A. Marto , Dipanjan Chowdhury , Sara J. Buhrlage","doi":"10.1016/j.chembiol.2025.08.002","DOIUrl":"10.1016/j.chembiol.2025.08.002","url":null,"abstract":"<div><div>Deubiquitinating enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed <strong>CAS-010</strong>, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor. We validated on-target effects of <strong>CAS-010</strong> on the negative regulation of p53 transactivation in the wild-type setting. We demonstrated that <strong>CAS-010</strong> disrupts the 53BP1-USP28 interaction, and more broadly showed that USP28 catalytic activity contributes to this key interaction. Taken together, <strong>CAS-010</strong> and the accompanying negative control compound <strong>WPT-086</strong> and inhibitor-resistant mutant provide well-validated tools for further characterizing the role of USP28 in p53-mediated effect on cell cycle control and cell fate.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1166-1182.e27"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928376","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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.009
Canyong Guo, Kurt Wüthrich
In an interview with Dr. Mishtu Dey, Editor-in-Chief of Cell Chemical Biology, the authors of the article entitled “Structural basis of Adenosine 2A Receptor balanced signaling activation relies on allosterically mediated structural dynamics” share their thoughts on technological advances in structural biology and how applications of genetic labeling techniques made it possible to probe into the core of a GPCR.
{"title":"Meet the authors: Canyong Guo and Kurt Wüthrich","authors":"Canyong Guo, Kurt Wüthrich","doi":"10.1016/j.chembiol.2025.08.009","DOIUrl":"10.1016/j.chembiol.2025.08.009","url":null,"abstract":"<div><div>In an interview with Dr. Mishtu Dey, Editor-in-Chief of <em>Cell Chemical Biology</em>, the authors of the article entitled “Structural basis of Adenosine 2A Receptor balanced signaling activation relies on allosterically mediated structural dynamics” share their thoughts on technological advances in structural biology and how applications of genetic labeling techniques made it possible to probe into the core of a GPCR.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1089-1090"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078422","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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.004
Tin-Yan Koo , Jason Ying Ki Li , Nga-Sze Lee , Jintian Chen , Hillary Yui-Yan Yip , Ianto Bosheng Huang , Kai-Yu Ng , Helen H.N. Yan , Suet Yi Leung , Stephanie Ma , Jingying Zhou , Clive Yik-Sham Chung
RhoA is a key cancer driver and potential colorectal cancer (CRC) therapy target but remains undrugged clinically. Using activity-based protein profiling (ABPP) and mass spectrometry (MS), we identified CL16, a covalent inhibitor targeting the unique Cys16 on RhoA subfamily, which confers high specificity over other Rho family proteins. Cys16 is adjacent to the nucleotide-binding pocket and switch regions, which are critical for RhoA function. The binding by CL16 effectively disrupts GTP binding and inhibits RhoA activity in CRC cells, leading to cytotoxic killing of CRC cells through cell-cycle arrest and apoptosis. In mouse CRC models, CL16 exhibits strong antitumor and antimetastatic effects, promotes T cell infiltration into the tumor microenvironment, and shows no observable toxicity. Our findings suggest that covalent targeting of the druggable Cys16 on RhoA offers a promising strategy for CRC treatment, providing a foundation for developing specific RhoA inhibitors for clinical application.
{"title":"A covalent inhibitor targeting Cys16 on RhoA in colorectal cancer","authors":"Tin-Yan Koo , Jason Ying Ki Li , Nga-Sze Lee , Jintian Chen , Hillary Yui-Yan Yip , Ianto Bosheng Huang , Kai-Yu Ng , Helen H.N. Yan , Suet Yi Leung , Stephanie Ma , Jingying Zhou , Clive Yik-Sham Chung","doi":"10.1016/j.chembiol.2025.08.004","DOIUrl":"10.1016/j.chembiol.2025.08.004","url":null,"abstract":"<div><div>RhoA is a key cancer driver and potential colorectal cancer (CRC) therapy target but remains undrugged clinically. Using activity-based protein profiling (ABPP) and mass spectrometry (MS), we identified CL16, a covalent inhibitor targeting the unique Cys16 on RhoA subfamily, which confers high specificity over other Rho family proteins. Cys16 is adjacent to the nucleotide-binding pocket and switch regions, which are critical for RhoA function. The binding by CL16 effectively disrupts GTP binding and inhibits RhoA activity in CRC cells, leading to cytotoxic killing of CRC cells through cell-cycle arrest and apoptosis. In mouse CRC models, CL16 exhibits strong antitumor and antimetastatic effects, promotes T cell infiltration into the tumor microenvironment, and shows no observable toxicity. Our findings suggest that covalent targeting of the druggable Cys16 on RhoA offers a promising strategy for CRC treatment, providing a foundation for developing specific RhoA inhibitors for clinical application.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1150-1165.e9"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996040","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}
Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.010
Raffaella De Pace, Chad D. Williamson, Juan S. Bonifacino
In an interview with Dr. Mishtu Dey, Editor-in-Chief of Cell Chemical Biology, the authors of the review article entitled “BLOC-1 and BORC: Complex regulators of endolysosomal dynamics” share their perspectives on how technological innovation and chemical biology approaches are advancing cell biology and neurobiology research, discuss their career paths, and share their thoughts on life as scientists.
{"title":"Meet the authors: Raffaella De Pace, Chad Williamson, and Juan Bonifacino","authors":"Raffaella De Pace, Chad D. Williamson, Juan S. Bonifacino","doi":"10.1016/j.chembiol.2025.08.010","DOIUrl":"10.1016/j.chembiol.2025.08.010","url":null,"abstract":"<div><div>In an interview with Dr. Mishtu Dey, Editor-in-Chief of <em>Cell Chemical Biology</em>, the authors of the review article entitled “BLOC-1 and BORC: Complex regulators of endolysosomal dynamics” share their perspectives on how technological innovation and chemical biology approaches are advancing cell biology and neurobiology research, discuss their career paths, and share their thoughts on life as scientists.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1091-1093"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078545","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}
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