Pub Date : 2025-09-18DOI: 10.1016/j.chembiol.2025.08.003
Zhiyong He , Yuyang Xie , Honglin Huang , Zhaoyu Zhang , Shenjiong Feng , Runda Xu , Xuancheng Chen , Fei Gao , Pan Li , Ming Zhu , Sen Wu , Xuguang Du
Genetic mutations are closely linked to human diseases, yet the relationship between many mutations and their corresponding phenotypes remains poorly understood. Furthermore, tools to study the connection between nucleotide variations and phenotypes are limited. To address this issue, we developed ACGBEmax by fusing the dual-functional deaminase, engineered N-methylpurine DNA glycosylase, and evolved SOS response associated peptidase domain with nCas9(D10A). ACGBEmax enables the precise conversion of A, C, and G to other bases in mammalian cells, thereby generating an extensive range of base mutations types. We used ACGBEmax to generate HPRT variants, identifying mutations conferring resistance to 6-thioguanine. Additionally, we performed in situ mutagenesis of Ctnnb1 in mouse liver, identifying both known and potential oncogenic mutations. Our results prove that ACGBEmax is a powerful tool for generating a wide spectrum of mutation types at specific gene loci, highlighting its significant potential for applications in functional screening and the directed evolution of protein variants.
{"title":"A base editor facilitates simultaneous purine and pyrimidine substitutions for ex vivo and in vivo mutagenesis screens","authors":"Zhiyong He , Yuyang Xie , Honglin Huang , Zhaoyu Zhang , Shenjiong Feng , Runda Xu , Xuancheng Chen , Fei Gao , Pan Li , Ming Zhu , Sen Wu , Xuguang Du","doi":"10.1016/j.chembiol.2025.08.003","DOIUrl":"10.1016/j.chembiol.2025.08.003","url":null,"abstract":"<div><div>Genetic mutations are closely linked to human diseases, yet the relationship between many mutations and their corresponding phenotypes remains poorly understood. Furthermore, tools to study the connection between nucleotide variations and phenotypes are limited. To address this issue, we developed ACGBEmax by fusing the dual-functional deaminase, engineered N-methylpurine DNA glycosylase, and evolved SOS response associated peptidase domain with nCas9(D10A). ACGBEmax enables the precise conversion of A, C, and G to other bases in mammalian cells, thereby generating an extensive range of base mutations types. We used ACGBEmax to generate HPRT variants, identifying mutations conferring resistance to 6-thioguanine. Additionally, we performed <em>in situ</em> mutagenesis of Ctnnb1 in mouse liver, identifying both known and potential oncogenic mutations. Our results prove that ACGBEmax is a powerful tool for generating a wide spectrum of mutation types at specific gene loci, highlighting its significant potential for applications in functional screening and the directed evolution of protein variants.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1183-1196.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987806","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.2025.08.011
Vsevolod V. Gurevich , Eugenia V. Gurevich
G protein-coupled receptors (GPCRs) regulate numerous physiological processes, and their activation promotes receptor interaction with G proteins, GPCR kinases, and arrestins. In this issue of Cell Chemical Biology, Guo et al.1 demonstrate that agonist-induced disorder on the cytoplasmic side enables this versatile coupling, revealing the molecular basis for GPCR activation mechanisms.
{"title":"Activation primes GPCRs for versatile coupling","authors":"Vsevolod V. Gurevich , Eugenia V. Gurevich","doi":"10.1016/j.chembiol.2025.08.011","DOIUrl":"10.1016/j.chembiol.2025.08.011","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) regulate numerous physiological processes, and their activation promotes receptor interaction with G proteins, GPCR kinases, and arrestins. In this issue of <em>Cell Chemical Biology</em>, Guo et al.<span><span><sup>1</sup></span></span> demonstrate that agonist-induced disorder on the cytoplasmic side enables this versatile coupling, revealing the molecular basis for GPCR activation mechanisms.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 9","pages":"Pages 1094-1096"},"PeriodicalIF":7.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078424","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 : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.002
Hannah C. Lloyd , Yuli Li , N. Connor Payne , Zhenguang Zhao , Wenqing Xu , Alena Kroupova , David Zollman , Tengfang Long , Farah Kabir , Mei Chen , Rebecca Freeman , Ethan Yang Feng , Sarah Y. Xi , Ya-Chieh Hsu , Alessio Ciulli , Ralph Mazitschek , Christina M. Woo
C-terminal cyclic imides are posttranslational modifications (PTMs) on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modifications across the proteome by mass spectrometry-based proteomics, an orthogonal and generalizable method to visualize the C-terminal cyclic imide would enhance detection, sensitivity, and throughput of endogenous CRBN substrate characterization. Here, we develop an antibody-like reagent, termed “cerebody,” for visualizing and enriching C-terminal cyclic imide-modified proteins. We describe the engineering of CRBN derivatives to produce cerebody and use it to identify CRBN substrates by western blot and enrichment from whole-cell and tissue lysates. CRBN substrates identified by cerebody enrichment are mapped, validated, and further characterized for dependence on the C-terminal cyclic imide modification. These methods will accelerate the characterization of endogenous CRBN substrates and their regulation.
{"title":"A method for the detection and enrichment of endogenous cereblon substrates","authors":"Hannah C. Lloyd , Yuli Li , N. Connor Payne , Zhenguang Zhao , Wenqing Xu , Alena Kroupova , David Zollman , Tengfang Long , Farah Kabir , Mei Chen , Rebecca Freeman , Ethan Yang Feng , Sarah Y. Xi , Ya-Chieh Hsu , Alessio Ciulli , Ralph Mazitschek , Christina M. Woo","doi":"10.1016/j.chembiol.2025.07.002","DOIUrl":"10.1016/j.chembiol.2025.07.002","url":null,"abstract":"<div><div>C-terminal cyclic imides are posttranslational modifications (PTMs) on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modifications across the proteome by mass spectrometry-based proteomics, an orthogonal and generalizable method to visualize the C-terminal cyclic imide would enhance detection, sensitivity, and throughput of endogenous CRBN substrate characterization. Here, we develop an antibody-like reagent, termed “cerebody,” for visualizing and enriching C-terminal cyclic imide-modified proteins. We describe the engineering of CRBN derivatives to produce cerebody and use it to identify CRBN substrates by western blot and enrichment from whole-cell and tissue lysates. CRBN substrates identified by cerebody enrichment are mapped, validated, and further characterized for dependence on the C-terminal cyclic imide modification. These methods will accelerate the characterization of endogenous CRBN substrates and their regulation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1028-1041.e13"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797385","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 : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.001
Yusheng Liu , Jiadiao Zhou , Yueji Wang , Daniel Nguyen , Dhyanesh Baskaran , Yuan Liu , Hua Wang
Metabolic glycoengineering of unnatural sugars provides a powerful tool to introduce unique chemical tags onto cell membrane for subsequent conjugation of cargos. However, the metabolic glycan labeling efficiency of antigen-presenting cells (APCs), the key mediators of adaptive immunity, is often low. Here, we report that APCs upregulate GlcNAc 2-epimerase (RENBP) and that RENBP inhibition leads to improved labeling efficiency of tetraacetyl-N-azidoacetylmannosamine (AAM) in APCs, including dendritic cells (1.2-fold), macrophages (1.3-fold), and B cells (1.4-fold) in vitro. RENBP inhibition can preferentially enhance AAM labeling efficiency in APCs than in non-APCs and selectively enhance the labeling efficiency of AAM over azido-galactosamine. We further demonstrate that RENBP inhibitors can improve AAM-mediated labeling of B cells and other APCs in vivo, with the largest enhancement for B cells (>3-fold) for 7 days. Our study uncovers a facile approach to improving metabolic glycan labeling of APCs, enabling the development of APC-targeted immunotherapies.
非天然糖的代谢糖工程为在细胞膜上引入独特的化学标签以进行后续的偶联提供了有力的工具。然而，作为适应性免疫的关键介质，抗原呈递细胞（antigen-presenting cells, APCs）的代谢聚糖标记效率往往较低。在这里，我们报道了apc上调GlcNAc 2- epimase (RENBP)，并且RENBP抑制导致apc(包括树突状细胞（1.2倍）、巨噬细胞（1.3倍）和B细胞（1.4倍）中四乙酰基- n -叠氮乙酰甘油三胺（AAM）的标记效率提高。RENBP抑制可以优先提高AAM在APCs中的标记效率，并选择性地提高AAM对叠氮半乳糖胺的标记效率。我们进一步证明，RENBP抑制剂可以在体内改善aam介导的B细胞和其他apc的标记，对B细胞的增强效果最大（3倍），持续7天。我们的研究揭示了一种简单的方法来改善apc的代谢聚糖标记，使apc靶向免疫疗法的发展成为可能。
{"title":"RENBP inhibition amplifies metabolic glycan labeling efficiency of antigen-presenting cells in vitro and in vivo","authors":"Yusheng Liu , Jiadiao Zhou , Yueji Wang , Daniel Nguyen , Dhyanesh Baskaran , Yuan Liu , Hua Wang","doi":"10.1016/j.chembiol.2025.07.001","DOIUrl":"10.1016/j.chembiol.2025.07.001","url":null,"abstract":"<div><div>Metabolic glycoengineering of unnatural sugars provides a powerful tool to introduce unique chemical tags onto cell membrane for subsequent conjugation of cargos. However, the metabolic glycan labeling efficiency of antigen-presenting cells (APCs), the key mediators of adaptive immunity, is often low. Here, we report that APCs upregulate GlcNAc 2-epimerase (RENBP) and that RENBP inhibition leads to improved labeling efficiency of tetraacetyl-<em>N</em>-azidoacetylmannosamine (AAM) in APCs, including dendritic cells (1.2-fold), macrophages (1.3-fold), and B cells (1.4-fold) <em>in vitro</em>. RENBP inhibition can preferentially enhance AAM labeling efficiency in APCs than in non-APCs and selectively enhance the labeling efficiency of AAM over azido-galactosamine. We further demonstrate that RENBP inhibitors can improve AAM-mediated labeling of B cells and other APCs <em>in vivo</em>, with the largest enhancement for B cells (>3-fold) for 7 days. Our study uncovers a facile approach to improving metabolic glycan labeling of APCs, enabling the development of APC-targeted immunotherapies.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 983-993.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792345","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 : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.005
Yayoi Natsume-Kitatani , Kouji Kobiyama , Yoshinobu Igarashi , Taiki Aoshi , Noriyuki Nakatsu , Lokesh P. Tripathi , Junichi Ito , Johan Nyström-Persson , Yuji Kosugi , Rodolfo S. Allendes Osorio , Chioko Nagao , Burcu Temizoz , Etsushi Kuroda , Daron M. Standley , Hiroshi Kiyono , Kenji Nakanishi , Satoshi Uematsu , Isao Hamaguchi , Yasuhiro Yasutomi , Jun Kunisawa , Ken J. Ishii
Adjuvants are immunostimulators used to enhance vaccine efficacy against infectious diseases. However, current methods for evaluating their efficacy and safety are limited, hindering large-scale screening. To address this, we developed a prototype Adjuvant Database (ADB) containing transcriptome data, generated using the same protocols as the widely used Open TG-GATEs (OTG) toxicogenomics database, covering 25 adjuvants across multiple species, organs, time points, and doses. This enabled cross-database integration of ADB and OTG. Transcriptomic patterns successfully distinguished each adjuvant regardless of organs or species. Using both databases, we built machine learning models to predict adjuvanticity and hepatotoxicity. Notably, we identified colchicine’s adjuvant activity and FK565’s liver toxicity through data-driven analysis. Overall, ADB combined with OTG offers a framework for transcriptomics-based, data-driven screening of adjuvant candidates.
{"title":"An adjuvant database for preclinical evaluation of vaccines and immunotherapeutics","authors":"Yayoi Natsume-Kitatani , Kouji Kobiyama , Yoshinobu Igarashi , Taiki Aoshi , Noriyuki Nakatsu , Lokesh P. Tripathi , Junichi Ito , Johan Nyström-Persson , Yuji Kosugi , Rodolfo S. Allendes Osorio , Chioko Nagao , Burcu Temizoz , Etsushi Kuroda , Daron M. Standley , Hiroshi Kiyono , Kenji Nakanishi , Satoshi Uematsu , Isao Hamaguchi , Yasuhiro Yasutomi , Jun Kunisawa , Ken J. Ishii","doi":"10.1016/j.chembiol.2025.07.005","DOIUrl":"10.1016/j.chembiol.2025.07.005","url":null,"abstract":"<div><div>Adjuvants are immunostimulators used to enhance vaccine efficacy against infectious diseases. However, current methods for evaluating their efficacy and safety are limited, hindering large-scale screening. To address this, we developed a prototype Adjuvant Database (ADB) containing transcriptome data, generated using the same protocols as the widely used Open TG-GATEs (OTG) toxicogenomics database, covering 25 adjuvants across multiple species, organs, time points, and doses. This enabled cross-database integration of ADB and OTG. Transcriptomic patterns successfully distinguished each adjuvant regardless of organs or species. Using both databases, we built machine learning models to predict adjuvanticity and hepatotoxicity. Notably, we identified colchicine’s adjuvant activity and FK565’s liver toxicity through data-driven analysis. Overall, ADB combined with OTG offers a framework for transcriptomics-based, data-driven screening of adjuvant candidates.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1075-1088.e3"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813235","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 : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.007
Weiyao Wang , Mehman Bunyatov , Deana Moffat , Natalia Lopez-Barbosa , Matthew P. DeLisa
Monoclonal antibodies (mAbs) that specifically recognize cell surface glycans associated with cancer and infectious disease hold tremendous value for basic research and clinical applications. However, high-quality anti-glycan mAbs with sufficiently high affinity and specificity remain scarce, highlighting the need for strategies that enable optimization of antigen-binding properties. To this end, we engineered the affinity of a polysialic acid (polySia)-specific antibody called mAb735, which possesses only modest affinity. Using a combination of rational design and directed evolution, we isolated several affinity-matured IgG variants with ∼5- to 7-fold stronger affinity for polySia relative to mAb735. The higher affinity IgG variants opsonized polySia-positive cancer cells more avidly and triggered greater antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Collectively, these results demonstrate the effective application of molecular evolution techniques to an important anti-glycan antibody, providing insights into its carbohydrate recognition and uncovering variants with greater therapeutic promise due to their enhanced affinity and potency.
{"title":"Engineering affinity-matured variants of an anti-polysialic acid monoclonal antibody with superior cytotoxicity-mediating potency","authors":"Weiyao Wang , Mehman Bunyatov , Deana Moffat , Natalia Lopez-Barbosa , Matthew P. DeLisa","doi":"10.1016/j.chembiol.2025.07.007","DOIUrl":"10.1016/j.chembiol.2025.07.007","url":null,"abstract":"<div><div>Monoclonal antibodies (mAbs) that specifically recognize cell surface glycans associated with cancer and infectious disease hold tremendous value for basic research and clinical applications. However, high-quality anti-glycan mAbs with sufficiently high affinity and specificity remain scarce, highlighting the need for strategies that enable optimization of antigen-binding properties. To this end, we engineered the affinity of a polysialic acid (polySia)-specific antibody called mAb735, which possesses only modest affinity. Using a combination of rational design and directed evolution, we isolated several affinity-matured IgG variants with ∼5- to 7-fold stronger affinity for polySia relative to mAb735. The higher affinity IgG variants opsonized polySia-positive cancer cells more avidly and triggered greater antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Collectively, these results demonstrate the effective application of molecular evolution techniques to an important anti-glycan antibody, providing insights into its carbohydrate recognition and uncovering variants with greater therapeutic promise due to their enhanced affinity and potency.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1042-1057.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879272","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 : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.006
Changfa Sun , Shilei Hao , Lili Wang , Run Meng , Hui Wang , Wenfeng Li , Jia Deng , Qiudan Yin , Xiaoliang Chen , Tingxiu Xiang , Zuojin Liu , Haiming Zheng , Zhongli Luo , Kaiyong Cai , Bochu Wang , Shuguang Zhang , Rui Qing
The CXCR4/CXCL12 axis is vital for tumor metastasis and immune evasion in various cancers. However, developing effective inhibitors is challenging due to complex intracellular interactions and limitations of soluble receptor drugs targeting single transmembrane proteins. Here, we engineered a water-soluble CXCR4QTY-Fc molecular trap by fusing a redesigned CXCR4 variant with the IgG1-Fc domain. CXCR4QTY-Fc effectively neutralizes CXCL12, inhibits CXCR4 downstream signaling, and suppresses migration and invasion of CXCR4-positive cancer cells in vitro, even with dipeptidyl peptidase 4 (DPP-4) inhibition. In mouse models of pancreatic, breast, and prostate cancer metastasis, CXCR4QTY-Fc significantly reduced tumor metastasis, outperforming the clinical CXCR4 antagonist AMD3100. Mechanistically, CXCR4QTY-Fc blocks endosomal CXCL12/CXCR4 signaling and reshapes the tumor microenvironment by downregulating CXCL12, thereby inhibiting tumor growth, metastasis, and angiogenesis. This biomimetic, non-immunogenic approach offers a promising strategy for broad-spectrum metastasis inhibition.
{"title":"Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4QTY-Fc as a molecular trap","authors":"Changfa Sun , Shilei Hao , Lili Wang , Run Meng , Hui Wang , Wenfeng Li , Jia Deng , Qiudan Yin , Xiaoliang Chen , Tingxiu Xiang , Zuojin Liu , Haiming Zheng , Zhongli Luo , Kaiyong Cai , Bochu Wang , Shuguang Zhang , Rui Qing","doi":"10.1016/j.chembiol.2025.07.006","DOIUrl":"10.1016/j.chembiol.2025.07.006","url":null,"abstract":"<div><div>The CXCR4/CXCL12 axis is vital for tumor metastasis and immune evasion in various cancers. However, developing effective inhibitors is challenging due to complex intracellular interactions and limitations of soluble receptor drugs targeting single transmembrane proteins. Here, we engineered a water-soluble CXCR4<sup>QTY</sup>-Fc molecular trap by fusing a redesigned CXCR4 variant with the IgG1-Fc domain. CXCR4<sup>QTY</sup>-Fc effectively neutralizes CXCL12, inhibits CXCR4 downstream signaling, and suppresses migration and invasion of CXCR4-positive cancer cells <em>in vitro</em>, even with dipeptidyl peptidase 4 (DPP-4) inhibition. In mouse models of pancreatic, breast, and prostate cancer metastasis, CXCR4<sup>QTY</sup>-Fc significantly reduced tumor metastasis, outperforming the clinical CXCR4 antagonist AMD3100. Mechanistically, CXCR4<sup>QTY</sup>-Fc blocks endosomal CXCL12/CXCR4 signaling and reshapes the tumor microenvironment by downregulating CXCL12, thereby inhibiting tumor growth, metastasis, and angiogenesis. This biomimetic, non-immunogenic approach offers a promising strategy for broad-spectrum metastasis inhibition.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1058-1074.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879273","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 : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.003
Yixin Sun , Baoyuan Zhang , Jiayao Wang , Xin Li , Zhonggui He , Chutong Tian , Bingjun Sun , Jin Sun
Designing highly selective nanomedicines with precise recognition of biological interfaces for efficient cancer therapy represents a tremendous challenge. Inspired by the inherent chirality and enantioselectivity of organisms, we constructed dynamic chiral cyclic diselenide-conjugated paclitaxel prodrug nanoassemblies (CSEPNs) to simulate the chiral recognition process. The optimal chiral configuration with potent antitumor effects was screened by deconstructing the lock-and-key biorecognition of CSEPNs. Compared with R-(−)-CSEP, S-(+)-CSEP displayed steady chirality-dependent self-assembly due to the balance of intermolecular interaction and steric hindrance. With ring-tensioned backbone and superior chiral topology, S-(+)-CSEPNs exhibited ultra-high redox sensitivity and enhanced clathrin-mediated endocytosis. More importantly, S-(+)-CSEPNs presented the in vivo transport advantages of high tumor accumulation and low excretion rate. Finally, CSEPNs exerted robust synergistic tumor suppression through chemotherapy, tumor redox axis modulation, and tumor angiogenesis inhibition. These findings confirmed the dominant role of chiral lock-and-key biorecognition in determining the biological fate of the nanomedicines.
{"title":"Robust antitumor treatment driven by lock-and-key biorecognition of dynamic cyclic diselenide-guided chiral prodrug self-assembly","authors":"Yixin Sun , Baoyuan Zhang , Jiayao Wang , Xin Li , Zhonggui He , Chutong Tian , Bingjun Sun , Jin Sun","doi":"10.1016/j.chembiol.2025.07.003","DOIUrl":"10.1016/j.chembiol.2025.07.003","url":null,"abstract":"<div><div>Designing highly selective nanomedicines with precise recognition of biological interfaces for efficient cancer therapy represents a tremendous challenge. Inspired by the inherent chirality and enantioselectivity of organisms, we constructed dynamic chiral cyclic diselenide-conjugated paclitaxel prodrug nanoassemblies (CSEPNs) to simulate the chiral recognition process. The optimal chiral configuration with potent antitumor effects was screened by deconstructing the lock-and-key biorecognition of CSEPNs. Compared with R-(−)-CSEP, S-(+)-CSEP displayed steady chirality-dependent self-assembly due to the balance of intermolecular interaction and steric hindrance. With ring-tensioned backbone and superior chiral topology, S-(+)-CSEPNs exhibited ultra-high redox sensitivity and enhanced clathrin-mediated endocytosis. More importantly, S-(+)-CSEPNs presented the <em>in vivo</em> transport advantages of high tumor accumulation and low excretion rate. Finally, CSEPNs exerted robust synergistic tumor suppression through chemotherapy, tumor redox axis modulation, and tumor angiogenesis inhibition. These findings confirmed the dominant role of chiral lock-and-key biorecognition in determining the biological fate of the nanomedicines.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 1013-1027.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813234","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 : 2025-08-21DOI: 10.1016/j.chembiol.2025.07.004
Wadie D. Mahauad-Fernandez , Yu Chi Yang , Ian Lai , Jangho Park , Lilian Yao , James W. Evans , Danielle F. Atibalentja , Xinyu Chen , Vishnupriya Kanakaveti , Zihui Zhao , G. Leslie Burnett , Bianca J. Lee , Nuntana Dinglasan , Nataliya Tovbis Shifrin , Ethan Ahler , Elsa Quintana , Adrian L. Gill , Jacqueline A.M. Smith , Mallika Singh , Dean W. Felsher
The MYC oncogene is causally involved in the pathogenesis of most human cancers. The mTORC1 complex regulates MYC translation through 4EBP1 and S6K. However, agents that selectively target mTORC1 (without affecting mTORC2) have so far failed to reactivate 4EBP1 and, thus, cannot effectively suppress MYC in vivo. In contrast, nonselective inhibitors that block both mTOR complexes can activate 4EBP1, but often lack tolerability and induce immunosuppression. Here, we introduce bi-steric mTORC1-selective inhibitors, including the clinical candidate RMC-5552, which potently reactivate 4EBP1 and decrease MYC protein expression levels. Consequently, suppression of MYC signaling occurs, resulting in tumor growth inhibition through both direct effects on tumor cells and immune activation. RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic MYC amplifications and reduces MYC protein levels in vivo. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression.
{"title":"Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers","authors":"Wadie D. Mahauad-Fernandez , Yu Chi Yang , Ian Lai , Jangho Park , Lilian Yao , James W. Evans , Danielle F. Atibalentja , Xinyu Chen , Vishnupriya Kanakaveti , Zihui Zhao , G. Leslie Burnett , Bianca J. Lee , Nuntana Dinglasan , Nataliya Tovbis Shifrin , Ethan Ahler , Elsa Quintana , Adrian L. Gill , Jacqueline A.M. Smith , Mallika Singh , Dean W. Felsher","doi":"10.1016/j.chembiol.2025.07.004","DOIUrl":"10.1016/j.chembiol.2025.07.004","url":null,"abstract":"<div><div>The <em>MYC</em> oncogene is causally involved in the pathogenesis of most human cancers. The mTORC1 complex regulates MYC translation through 4EBP1 and S6K. However, agents that selectively target mTORC1 (without affecting mTORC2) have so far failed to reactivate 4EBP1 and, thus, cannot effectively suppress MYC <em>in vivo.</em> In contrast, nonselective inhibitors that block both mTOR complexes can activate 4EBP1, but often lack tolerability and induce immunosuppression. Here, we introduce bi-steric mTORC1-selective inhibitors, including the clinical candidate RMC-5552, which potently reactivate 4EBP1 and decrease MYC protein expression levels. Consequently, suppression of MYC signaling occurs, resulting in tumor growth inhibition through both direct effects on tumor cells and immune activation. RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic <em>MYC</em> amplifications and reduces MYC protein levels <em>in vivo</em>. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 8","pages":"Pages 994-1012.e11"},"PeriodicalIF":7.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819450","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 : 2025-07-17DOI: 10.1016/j.chembiol.2025.05.012
Wenjun Fan , Hester Liu , Gregory C. Stachelek , Asma Begum , Catherine E. Davis , Tony E. Dorado , Glen Ernst , William C. Reinhold , Busra Ozbek , Qizhi Zheng , Angelo M. De Marzo , N.V. Rajeshkumar , James C. Barrow , Marikki Laiho
Ribosome biosynthesis is a cancer vulnerability targeted by inhibiting RNA polymerase I (Pol I) transcription. We developed specific Pol I inhibitors that activate a ribotoxic stress pathway to uncover drivers of sensitivity. Integrating multi-omics and drug response data from a large cancer cell panel, we found that RPL22 frameshift mutations confer Pol I inhibitor sensitivity. Mechanistically, RPL22 interacts directly with 28S rRNA and mRNA splice junctions, acting as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promotes splicing of its paralog RPL22L1 and the p53 negative regulator MDM4. Both chemical and genetic inhibition of rRNA synthesis broadly remodel mRNA splicing controlling hundreds of targets. Notably, RPL22-dependent alternative splicing is reversed by Pol I inhibition, revealing a non-canonical ribotoxic stress-initiated tumor suppressive pathway. This study uncovers a robust mechanism linking rRNA synthesis activity to splicing, coordinated by the ribosomal protein RPL22.
{"title":"Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22","authors":"Wenjun Fan , Hester Liu , Gregory C. Stachelek , Asma Begum , Catherine E. Davis , Tony E. Dorado , Glen Ernst , William C. Reinhold , Busra Ozbek , Qizhi Zheng , Angelo M. De Marzo , N.V. Rajeshkumar , James C. Barrow , Marikki Laiho","doi":"10.1016/j.chembiol.2025.05.012","DOIUrl":"10.1016/j.chembiol.2025.05.012","url":null,"abstract":"<div><div>Ribosome biosynthesis is a cancer vulnerability targeted by inhibiting RNA polymerase I (Pol I) transcription. We developed specific Pol I inhibitors that activate a ribotoxic stress pathway to uncover drivers of sensitivity. Integrating multi-omics and drug response data from a large cancer cell panel, we found that RPL22 frameshift mutations confer Pol I inhibitor sensitivity. Mechanistically, RPL22 interacts directly with 28S rRNA and mRNA splice junctions, acting as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promotes splicing of its paralog RPL22L1 and the p53 negative regulator MDM4. Both chemical and genetic inhibition of rRNA synthesis broadly remodel mRNA splicing controlling hundreds of targets. Notably, RPL22-dependent alternative splicing is reversed by Pol I inhibition, revealing a non-canonical ribotoxic stress-initiated tumor suppressive pathway. This study uncovers a robust mechanism linking rRNA synthesis activity to splicing, coordinated by the ribosomal protein RPL22.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 908-925.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311709","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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