ACS Pharmacology and Translational Science最新文献_第10页

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-07-11

Xiaotian Ji, Changying Shi, Dekai Yuan, Minghao Luo, Liye Suo, Xiguang Yang, Dandan Guo, Norifumi Urao, Robert Cooney and Juntao Luo*,

引用次数: 0

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-07-11

Antonella Rocchi, Tambet Teesalu* and Christian Celia*,

引用次数: 0

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-07-11

引用次数: 0

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-07-11

Vojtech Novohradsky, Alicia Marco, Marie Svitelova, Natalia Cutillas, José Ruiz* and Viktor Brabec*,

引用次数: 0

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-07-11

John A. Bumpus*,

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Benzestrol Isomer Stereochemistry Determines the Distinct Estrogenic Activities and Conformations of the Eight Isomers When Bound to Estrogen Receptor α 苯雌酚同分异构体立体化学决定了八种同分异构体与雌激素受体α结合时不同的雌激素活性和构象

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2025-07-09 DOI: 10.1021/acsptsci.5c00117

Yingwei Hou, Jerome C. Nwachukwu, Kathryn Carlson, Sung Hoon Kim, Samantha Angle, Eric N. Jacobsen, Toby Woods, Sofia L. Mateus, Sean W. Fanning, Yvonne Ziegler, Benita S. Katzenellenbogen, Kendall W. Nettles and John A. Katzenellenbogen*,

{"title":"Benzestrol Isomer Stereochemistry Determines the Distinct Estrogenic Activities and Conformations of the Eight Isomers When Bound to Estrogen Receptor α","authors":"Yingwei Hou, Jerome C. Nwachukwu, Kathryn Carlson, Sung Hoon Kim, Samantha Angle, Eric N. Jacobsen, Toby Woods, Sofia L. Mateus, Sean W. Fanning, Yvonne Ziegler, Benita S. Katzenellenbogen, Kendall W. Nettles and John A. Katzenellenbogen*, ","doi":"10.1021/acsptsci.5c00117","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00117","url":null,"abstract":"The nonsteroidal estrogen, benzestrol, has potent estrogenic activity, and through a recent stereocontrolled synthesis, we have obtained all eight of its constituent stereoisomers. We find that only one of them, RSS benzestrol, has very high binding affinity for estrogen receptor alpha (ERα); the other seven isomers have 60 to 600-fold lower affinity. We now show that the potencies of the isomers in two cell activity assays, proliferation of ER-positive breast cancer cells and stimulation of estrogenic gene activity, reflect their varying binding affinities for ERα. The crystal structure of the RSS isomer itself is consistent with its presumed absolute configuration and also reveals its conformational flexibility within the solid crystal lattice. We modeled each of the 8 benzestrol stereoisomers bound to ERα. Their calculated binding energies and internal torsional energies grouped with their experimentally measured binding affinities and biological activities, and the conformation for the highest affinity RSS isomer bound to ERα maps closely onto the conformation of the ERα-bound potent nonsteroidal estrogen, trans-diethylstilbestrol. Hence, we now provide a structural context for this congeneric series of benzestrol stereoisomers by proposing energy-based conformations they adopt when bound to ERα that underlie their effectiveness as estrogens.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2526–2535"},"PeriodicalIF":3.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic Potential of a Gadolinium Chelate Complex Conjugated with Vanillic Acid for Alzheimer’s Disease 钆-香草酸螯合物对阿尔茨海默病的治疗潜力

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2025-07-08 DOI: 10.1021/acsptsci.5c00316

Min-Tae Jeon, Bokyung Sung, Jong Wook Lee, Dong Wook Hwang, Eunshil Lee, Hee-Kyung Kim, Dong-Kyu Kim, Do-Geun Kim* and Yongmin Chang*,

{"title":"Therapeutic Potential of a Gadolinium Chelate Complex Conjugated with Vanillic Acid for Alzheimer’s Disease","authors":"Min-Tae Jeon, Bokyung Sung, Jong Wook Lee, Dong Wook Hwang, Eunshil Lee, Hee-Kyung Kim, Dong-Kyu Kim, Do-Geun Kim* and Yongmin Chang*, ","doi":"10.1021/acsptsci.5c00316","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00316","url":null,"abstract":"Magnetic resonance imaging (MRI) is a widely used diagnostic tool for neurodegenerative diseases, including Alzheimer’s disease. A gadolinium chelate conjugated with vanillic acid (Gd-DO3A-Va) serves as a contrast agent that specifically targets activated microglia in the brains of Alzheimer’s disease animal models, such as the 5XFAD mouse. In this study, we evaluated the therapeutic potential of Gd-DO3A-Va in this model. The 5XFAD mouse exhibits neuroinflammation, characterized by activation of the c-Jun N-terminal kinase signaling pathway, inflammasome activation, and increased amyloid-β (Aβ) production─all of which are pathological features of Alzheimer’s disease. Treatment with Gd-DO3A-Va reduced inflammatory responses and Aβ deposits. Additionally, the peri-plaque dendritic loss observed in the brains of 5XFAD mice was attenuated following Gd-DO3A-Va treatment. Moreover, Gd-DO3A-Va treatment prevented memory loss, as indicated by the Y-maze test. Taken together, these findings suggest that Gd-DO3A-Va, an MR contrast agent that provides disease-specific signal enhancement in the brains of animal models of Alzheimer’s disease, shows promising therapeutic potential for preventing disease progression by suppressing inflammation and inhibiting Aβ production. Therefore, Gd-DO3A-Va could serve as a theranostic agent for Alzheimer’s disease.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2725–2735"},"PeriodicalIF":3.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development and Use of a Galectin-1-Specific Nanobody for Tumor Imaging and Elucidating the Role of Galectin-1 in Cancer 半乳糖凝集素-1特异性纳米体在肿瘤成像中的开发和应用，以及半乳糖凝集素-1在癌症中的作用

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2025-07-08 DOI: 10.1021/acsptsci.5c00178

Philippine GrangerJoly de Boissel, Rita Nehmé, Marlène Fortier, Myriam Létourneau, Brigitte Guérin, Véronique Dumulon-Perreault, Samia Ait-Mohand, Otman Sarrhini, Camille Fuselier, Alyssa Dumoulin, David Chatenet, Nicolas Doucet and Yves St-Pierre*,

{"title":"Development and Use of a Galectin-1-Specific Nanobody for Tumor Imaging and Elucidating the Role of Galectin-1 in Cancer","authors":"Philippine GrangerJoly de Boissel, Rita Nehmé, Marlène Fortier, Myriam Létourneau, Brigitte Guérin, Véronique Dumulon-Perreault, Samia Ait-Mohand, Otman Sarrhini, Camille Fuselier, Alyssa Dumoulin, David Chatenet, Nicolas Doucet and Yves St-Pierre*, ","doi":"10.1021/acsptsci.5c00178","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00178","url":null,"abstract":"Galectin-1 (GAL-1) plays a crucial role in cancer biology, especially in triple-negative breast cancer (TNBC), where it facilitates immune evasion and tumor progression. This study presents G1N1, a novel nanobody that specifically targets GAL-1 and exhibits remarkable affinity and selectivity. G1N1 effectively inhibits GAL-1-induced apoptosis in T cells while leaving GAL-7-induced apoptosis unaffected. Preclinical positron emission tomography (PET) imaging studies indicate that the radiolabeled [64Cu]Cu-NOTA-G1N1 accumulates significantly in breast cancer tumors, highlighting its potential for diagnostic imaging and therapeutic monitoring. Transcriptomic analyses suggest that G1N1 may counteract GAL-1-induced immunosuppression and downregulate chemoresistance-associated genes, particularly those involved in the NF-κB/TNFα signaling pathway, while also decreasing the expression of prometastatic genes like MMP-3. In conclusion, G1N1’s dual functionality as a diagnostic and therapeutic agent emphasizes its promise in personalized medicine, potentially enhancing clinical management strategies for TNBC and other aggressive cancers","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2564–2574"},"PeriodicalIF":3.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models 针对代谢脆弱性揭示己糖激酶2是非小细胞肺癌模型中对奥西替尼耐药的关键媒介

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2025-07-08 DOI: 10.1021/acsptsci.5c00235

Yizhen Guo, Ding Huang, Yan Zhou, Maoxin Ran, Shaolin Zhang and Kin Yip Tam*,

{"title":"Targeting Metabolic Vulnerabilities Reveals Hexokinase 2 as a Key Mediator of Resistance to Osimertinib in Non-Small Cell Lung Cancer Models","authors":"Yizhen Guo, Ding Huang, Yan Zhou, Maoxin Ran, Shaolin Zhang and Kin Yip Tam*, ","doi":"10.1021/acsptsci.5c00235","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00235","url":null,"abstract":"Acquired resistance to osimertinib (OSI) poses a significant challenge in the treatment of epidermal growth factor receptor mutant non-small cell lung cancer (NSCLC). Although OSI is effective as a first-line salvage therapy in T790M-positive patients following progression on first- or second-generation EGFR-TKIs (erlotinib, gefitinib, and afatinib), the inevitable development of acquired resistance limits its therapeutic efficacy. This study reveals that OSI-resistant (OSIR) NSCLC cells underwent metabolic reprogramming characterized by enhanced glycolysis and upregulation of hexokinase 2 (HK2). We demonstrated that HK2 inhibitor, benserazide, exhibited significant anticancer effects in OSIR cell models and mediated by reactive oxygen species. Our results suggested that HK2 inhibition effectively modulated the enhanced glycolysis, activated the AMPK-mTOR-autophagy axis, and unexpectedly interfered with NF-κB signaling through direct HK2-IKKβ interaction. Excitingly, the protein expression level and activity of pyruvate dehydrogenase kinase 1 (PDK1) in OSIR cells were upregulated upon HK2 inhibition, indicating a pro-survival role. Combined inhibition of HK2 and PDK1 synergistically inhibited the proliferation of OSIR cells and significantly suppressed tumor growth in an OSIR cell xenograft model, outperforming the single use of HK2 inhibitor. This combination successfully rectified aberrant glucose metabolism and enhanced oxidative phosphorylation. Our findings identified HK2 as a crucial mediator in overcoming OSI resistance and suggested that combined inhibition of HK2 and PDK1 could be a promising approach in OSIR NSCLC.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2646–2662"},"PeriodicalIF":3.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antineuroblastoma Activity Evaluation and Mechanism of Novel PD-L1 Small Molecule Inhibitors through Immune and Non-Immune Pathways 新型PD-L1小分子抑制剂通过免疫和非免疫途径抗神经母细胞瘤活性评价及其机制

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2025-07-07 DOI: 10.1021/acsptsci.5c00226

Jianwei Wang, Yongnan Zhou, Zejie Chen, Xiaoyin Zhao, Haoran Xu, Feng Zhang, Awadasseid Annoor, Rui Wang, Caiyun Wu, Hua Zhang, Mengyu Zhu and Wen Zhang*,

{"title":"Antineuroblastoma Activity Evaluation and Mechanism of Novel PD-L1 Small Molecule Inhibitors through Immune and Non-Immune Pathways","authors":"Jianwei Wang, Yongnan Zhou, Zejie Chen, Xiaoyin Zhao, Haoran Xu, Feng Zhang, Awadasseid Annoor, Rui Wang, Caiyun Wu, Hua Zhang, Mengyu Zhu and Wen Zhang*, ","doi":"10.1021/acsptsci.5c00226","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00226","url":null,"abstract":"Neuroblastoma (NB) is a pediatric solid tumor originating in the sympathetic nervous system, primarily affecting children under 10 years old. Metastatic, high-risk NB often exhibits elevated PD-L1 expression, which is linked to poor prognosis. In this study, we screened 41 newly synthesized biphenyl small molecules for activity against PD-L1 highly expressed NB cell lines. Compound SF-9-2 demonstrated the strongest inhibition of PD-L1/PD-1 binding, with an IC50 of 24.9 nM. Additionally, SF-9-2 effectively suppressed the viability of the PD-L1-high SK-N-SH cell line at 5.90 μM. SF-9-2 inhibited epithelial-to-mesenchymal transition, migration, invasion, and proliferation of SK-N-SH cells. It also induced apoptosis and cell cycle arrest. Mechanistic studies revealed that PD-L1 promotes SK-N-SH cell growth via the MAPK signaling pathway. This pro-growth effect was blocked by SF-9-2, and the inhibitory action of SF-9-2 could be reversed by an ERK-specific inhibitor. SF-9-2 further restored GSK-3β activity, enhancing PD-L1 degradation through the ubiquitin-proteasome pathway. More importantly, SF-9-2 significantly inhibited tumor growth in the SK-N-SH NOG mouse model (TGI: 69.45% at 40 mg/kg, i.p.) with no evident toxicity. SF-9-2 also acted as an immune checkpoint inhibitor, blocking PD-L1 to restore T cell function. These findings suggest that SF-9-2 inhibits neuroblastoma growth via both nonimmune and immune mechanisms, providing a promising therapeutic approach for NB.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 8","pages":"2612–2629"},"PeriodicalIF":3.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0