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}
Pub Date : 2025-07-17DOI: 10.1016/j.chembiol.2025.06.006
Riley J. Wedan , Sara M. Nowinski
Mitochondrial NADPH is abundant, but the reason why was uncertain. In a study published in Nature Cell Biology, Kim et al.1 identified an important role of NADK2-derived mitochondrial NADPH in mitochondrial fatty acid synthesis (mtFAS) through direct quantification of the products built by mtFAS. This work opens the door to understanding how NADK2, mitochondrial NADPH, and mtFAS regulate mitochondrial function.
{"title":"Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism","authors":"Riley J. Wedan , Sara M. Nowinski","doi":"10.1016/j.chembiol.2025.06.006","DOIUrl":"10.1016/j.chembiol.2025.06.006","url":null,"abstract":"<div><div>Mitochondrial NADPH is abundant, but the reason why was uncertain. In a study published in <em>Nature Cell Biology</em>, Kim et al.<span><span><sup>1</sup></span></span> identified an important role of NADK2-derived mitochondrial NADPH in mitochondrial fatty acid synthesis (mtFAS) through direct quantification of the products built by mtFAS. This work opens the door to understanding how NADK2, mitochondrial NADPH, and mtFAS regulate mitochondrial function.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 902-904"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645370","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.2025.06.001
Kenyon Weis , Omar Abdel-Wahab
In this issue of Cell Chemical Biology, Fan et al.1 identify that mutations in the ribosomal protein RPL22 confer sensitivity to RNA polymerase I inhibitors. RPL22 regulates MDM4 function and cell death via splicing of the MDM4 mRNA. These findings connect ribosome biogenesis with RNA splicing through RPL22.
{"title":"RPL22 links ribosome biogenesis, RNA splicing, and sensitivity to RNA polymerase I inhibition","authors":"Kenyon Weis , Omar Abdel-Wahab","doi":"10.1016/j.chembiol.2025.06.001","DOIUrl":"10.1016/j.chembiol.2025.06.001","url":null,"abstract":"<div><div>In this issue of <em>Cell Chemical Biology,</em> Fan et al.<span><span><sup>1</sup></span></span> identify that mutations in the ribosomal protein RPL22 confer sensitivity to RNA polymerase I inhibitors. RPL22 regulates MDM4 function and cell death via splicing of the MDM4 mRNA. These findings connect ribosome biogenesis with RNA splicing through RPL22.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 899-901"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645369","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}
Induced proximity using small molecules, exemplified by targeted protein degradation (TPD), represents a highly promising therapeutic strategy with significant untapped potential. However, evaluating an induced proximity event that accurately reflects drug binding typically requires the challenging and costly development of specific ligands, which limits the advancement of medicines based on this modality. To overcome this bottleneck, we combine genetic code expansion with ultra-fast bioorthogonal chemistry to sensitize specific protein sites at single-residue resolution to a generic bioorthogonal proximity inducer (BPI) molecule. Mammalian cells expressing sensitized mutants of the ubiquitin E3 ligases VHL and CRBN exhibit neosubstrate degradation in the presence of a BPI equipped with a ligand targeting bromodomain and extraterminal (BET) proteins. Furthermore, we demonstrate E3-independent degradation through recruitment of an upstream E2 conjugating enzyme. We anticipate that this approach will have broad applicability, enabling comprehensive assessment of the scope of induced proximity.
{"title":"Site-resolved assessment of targeted protein degradation","authors":"Ricardo Moreno-Ballesteros , Thomas Pembridge , Gaurav Beniwal , Satpal Virdee","doi":"10.1016/j.chembiol.2025.06.002","DOIUrl":"10.1016/j.chembiol.2025.06.002","url":null,"abstract":"<div><div>Induced proximity using small molecules, exemplified by targeted protein degradation (TPD), represents a highly promising therapeutic strategy with significant untapped potential. However, evaluating an induced proximity event that accurately reflects drug binding typically requires the challenging and costly development of specific ligands, which limits the advancement of medicines based on this modality. To overcome this bottleneck, we combine genetic code expansion with ultra-fast bioorthogonal chemistry to sensitize specific protein sites at single-residue resolution to a generic bioorthogonal proximity inducer (BPI) molecule. Mammalian cells expressing sensitized mutants of the ubiquitin E3 ligases VHL and CRBN exhibit neosubstrate degradation in the presence of a BPI equipped with a ligand targeting bromodomain and extraterminal (BET) proteins. Furthermore, we demonstrate E3-independent degradation through recruitment of an upstream E2 conjugating enzyme. We anticipate that this approach will have broad applicability, enabling comprehensive assessment of the scope of induced proximity.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 969-981.e7"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547594","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.2025.06.005
Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi
Aberrant NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective cereblon (CRBN) glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent interleukin-1β (IL-1β) release in vitro only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse in vivo. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.
{"title":"A cereblon-based glue degrader of NEK7 regulates NLRP3 inflammasome in a context-dependent manner","authors":"Aude Sylvain , Natacha Stoehr , Fupeng Ma , Artiom Cernijenko , Martin Schröder , Maryam Khoshouei , Melanie Vogelsanger , Michel Schoenboerner , Ashley Burke , Pasupuleti Rao , Jonathan M. Solomon , Joshiawa Paulk , Lei Xu , Janet Dawson , Damien Begue , Peggy Lefeuvre , Erik Ahrne , Andreas Hofmann , Callum J. Dickson , Philip Arabin , Zuni I. Bassi","doi":"10.1016/j.chembiol.2025.06.005","DOIUrl":"10.1016/j.chembiol.2025.06.005","url":null,"abstract":"<div><div>Aberrant NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective cereblon (CRBN) glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent interleukin-1β (IL-1β) release <em>in vitro</em> only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse <em>in vivo</em>. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 955-968.e13"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586803","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.2025.06.007
Zeba Rizvi , Gabriel C. Lander
The E3 ligase complex SIFI silences the integrated stress response (ISR) by targeting stress-induced proteins for degradation. In the May 6th issue of Nature, Yang et al.1 revealed how this megadalton complex recognizes diverse substrates and coordinates ubiquitin chain formation. Their insights into the ISR shutdown mechanism suggest new avenues for modulating stress responses in neurodegenerative disease.
{"title":"Silencing stress: Structural insights into ISR termination by the SIFI ubiquitin ligase","authors":"Zeba Rizvi , Gabriel C. Lander","doi":"10.1016/j.chembiol.2025.06.007","DOIUrl":"10.1016/j.chembiol.2025.06.007","url":null,"abstract":"<div><div>The E3 ligase complex SIFI silences the integrated stress response (ISR) by targeting stress-induced proteins for degradation. In the May 6<sup>th</sup> issue of <em>Nature</em>, Yang et al.<span><span><sup>1</sup></span></span> revealed how this megadalton complex recognizes diverse substrates and coordinates ubiquitin chain formation. Their insights into the ISR shutdown mechanism suggest new avenues for modulating stress responses in neurodegenerative disease.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 7","pages":"Pages 905-907"},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645526","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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