Drug Development Research最新文献

{"title":"Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia","authors":"Jin Yang,&nbsp;Yan Zhang,&nbsp;Yue-Chu Li,&nbsp;Qing-Xin Wang,&nbsp;Meng-Yuan Zhang,&nbsp;Yu-Jing Xu,&nbsp;Jing-Jing Wang,&nbsp;Xiao-Ting Liang,&nbsp;Xiao-Long Jing,&nbsp;Shuang-Shuang Zhou,&nbsp;Qing-Qing Li,&nbsp;Zi-Xuan Wang,&nbsp;Yun Zhou,&nbsp;Nuo Qiao,&nbsp;Tian-Hua Wei,&nbsp;Ning Ding,&nbsp;Xin Xue,&nbsp;Yan-Cheng Yu,&nbsp;Xiao-Long Wang,&nbsp;Shan-Liang Sun,&nbsp;Wei-Chen Dai,&nbsp;Nian-Guang Li,&nbsp;Zhi-Hao Shi","doi":"10.1002/ddr.70022","DOIUrl":"https://doi.org/10.1002/ddr.70022","url":null,"abstract":"<div>\u0000 \u0000 <p>The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure–activity relationships (SAR) analysis indicated that <b>FW-1</b> exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC₅₀ = 2.68 μM) and MOLM-13 (IC₅₀ = 1.03 μM). In our cellular mechanistic studies, <b>FW-1</b> also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces <b>FW-1</b> as a promising lead for type I FLT3 inhibitor, warranting further optimization.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling Immunotherapy Evasion in Lung Cancer: The Role of Fanconi Anemia and Stemness Genes in Shaping an Immunosuppressive Microenvironment","authors":"Haixia Wu,&nbsp;Yilin Yu,&nbsp;Hailun Huang,&nbsp;Gen Lin,&nbsp;Wei Wang,&nbsp;Jianyuan Huang,&nbsp;Zhaojun Yu,&nbsp;Deju Ye,&nbsp;Wu Chi,&nbsp;Xing Lin","doi":"10.1002/ddr.70020","DOIUrl":"https://doi.org/10.1002/ddr.70020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>The study aimed to investigate the fanconi anemia (FA)-related and stemness-related genes in lung cancer (LC) patients. Firstly, we identified stemness-related genes through weighted gene co-expression network analysis combined with TCGA database. Further combined stemness-related genes with FA-related genes to screen for prognostic-related genes. Risk score was constructed from the screened genes and comprehensive bioinformatics analyses were performed. Finally, single-cell data and in vitro experiment were used to validate our results. We screened a total of eight genes to construct a risk score. The risk score was an independent prognostic factor for LC. The validation results of multiple GEO databases were consistent with our results. Functional and pathway enrichment analysis showed that risk score was associated with cell cycle, DNA replication, DNA damage repair, and immune-related pathways. The results showed to be related to the stem cell self-renewal and proliferation. Besides, we also found that patients with higher risk scores had lower immune activity and function, and the effectiveness of immunotherapy might be poorer, with a higher rate of immune escape. Finally, our results revealed that SLC2A1 had the highest correlation with B cells in single-cell data analysis, and we validated its correlation with B cells and its expression with FA-related genes, tumor invasiveness, stemness, and drug sensitivity. Our research constructed a risk score based on FA-related and tumor stemness-related specific genes. In addition to accurately predicting the prognosis of patients with LC, the risk score may also serve as an innovative and viable predictor of immunotherapy response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formulation and Characterization of RBCS Coated Carboplatin Loaded Nano-Liposomal Formulation for Managing Breast Cancer","authors":"Akhilesh Dubey,&nbsp;Faby Raju,&nbsp;Cynthia Lizzie Lobo,&nbsp;Ravi Gs,&nbsp;Srinivas Hebbar,&nbsp;Amitha Shetty,&nbsp;Pankaj Kumar,&nbsp;Sally A. El-Zahaby","doi":"10.1002/ddr.70019","DOIUrl":"10.1002/ddr.70019","url":null,"abstract":"<div>\u0000 \u0000 <p>Cell membrane-coated Nano-Liposomes (CM-NLPs) offer a promising approach that combines the advantages of both host cells and synthetic nano-liposomes (NLPs). This technique involves coating liposomes with red blood cell (RBC) membranes to enhance their functionality. In this study, novel carboplatin-loaded NLPs (CP-NLPs) were formulated using phospholipids (Soya Phosphatidyl Choline) and cholesterol through the thin-film hydration method, and optimized using a 3² full factorial design. The optimized CP-NLPs were coated with RBC membranes, resulting in the formulation “CP-RBCs-NLPs.” These were characterized for particle size, zeta potential, entrapment efficiency, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), protein content, in vitro drug release, cell viability, and stability. The optimized CP-RBCs-NLPs exhibited a particle size of 103.6 nm, with zeta potential values of −27.3 mV indicating good stability. The entrapment efficiency was approximately 56%, and the drug release profile showed sustained release for up to 8 h. Cytotoxicity studies in human triple-negative breast cancer (MDA-MB468) cell lines demonstrated that CP-RBCs-NLPs effectively delivered the drug into target cells, facilitating cell death due to their bilayer structure similar to cell membranes. Overall, CP-RBCs-NLPs outperformed both carboplatin-loaded conventional NLPs (CP-CNLPs) and carboplatin-conventional solution (CP-CNS), making it a superior formulation for drug delivery.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Ester-Containing Azole Derivatives With Potent Anti-Candida Effects: Synthesis, Antifungal Susceptibility, Cytotoxicity, and Molecular Modeling Studies","authors":"Yusuf Ataker,&nbsp;Özge Öncü,&nbsp;Dolunay Gülmez,&nbsp;Suna Sabuncuoğlu,&nbsp;Sevtap Arikan-Akdagli,&nbsp;Suat Sari","doi":"10.1002/ddr.70021","DOIUrl":"10.1002/ddr.70021","url":null,"abstract":"<div>\u0000 \u0000 <p>Mortalities due to mycoses have dramatically increased with the emergence of drug-resistant strains and growing immune-compromised populations globally. Azole antifungals have been the first choice against fungal infections of a wide spectrum and several azole derivatives with ester function were reported for their potentially promising and favorable activity against <i>Candida</i> spp. In this study, we designed and synthesized a series of 1-(aryl)−2-(1<i>H</i>-imidazol-1-yl/1<i>H</i>-1,2,4-triazol-1-yl)ethyl esters, and tested them against seven reference <i>Candida</i> strains using EUCAST reference microdilution method. Among the series, <b>6a</b>, <b>6d</b>, and <b>6g</b> proved highly potent in vitro compared to fluconazole; especially against <i>Candida albicans</i> and <i>Candida tropicalis</i> with minimum inhibitor concentration (MIC) values as low as 0.125 and 0.06 mg/L, respectively, although their activities against <i>Candida krusei</i> and <i>Candida glabrata</i> remained limited. The compounds also showed minimal toxicity to murine fibroblasts according to the in vitro cytotoxicity tests. Molecular modeling predicted <b>6g</b> as an orally available druglike compound according to all parameters and CYP51 inhibition as the likely mechanism for their antifungal effects. The study underpins the promise of azoles with ester functionality as a potential scaffold for small-molecule antifungal drug design.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ambroxol Improves Amyloidogenic, NF-κB, and Nrf2 Pathways in a Scopolamine-Induced Cognitive Impairment Rat Model of Alzheimer's Disease","authors":"Khushboo Govind Faldu,&nbsp;Jigna Samir Shah","doi":"10.1002/ddr.70017","DOIUrl":"10.1002/ddr.70017","url":null,"abstract":"<div>\u0000 \u0000 <p>Ambroxol (ABX) is used to manage excessive production of mucus in the respiratory system. The present study sought to assess the neuroprotective potential of ambroxol by influencing the amyloidogenic, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in a rat model of Alzheimer's disease (AD) induced by scopolamine. The AD pathology was induced by chronic administration of scopolamine. The rats were given scopolamine at a dose of 2 mg/kg via intraperitoneal injection daily for 14 days, followed by treatment (ABX 121.5, 135, and 180 mg/kg orally and 5 mg/kg orally of donepezil) for the next 28 days while continuing to receive daily scopolamine injection. The behavior of the rats was evaluated using Modified Y-Maze and Novel object recognition tasks. Analyses were carried out on AD pathological markers [Amyloid beta peptide 1-40, Amyloid beta peptide 1-42, acetylcholinesterase, beta-secretase 1 (BACE1), total tau, and p-tau], inflammatory markers [NF-κB, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interferon γ], antioxidant markers (Nrf2 and heme Oxygenase 1 (HO-1)], along with synaptophysin and glial fibrillary acidic protein (GFAP) immunohistochemistry and histopathological assessment of the hippocampus. Our findings indicated that ABX reduced impairment in behavior. Levels of Acetylcholinesterase, BACE1, amyloid beta 1-40, amyloid beta 1-42, total tau, p-tau, NF-κB, IFN-γ, IL-6, and TNF-α decreased significantly. There was a significant increase in the levels of HO-1 and Nrf2. It stopped the neuronal degeneration, raised synaptophysin immunoreactivity, and lowered GFAP immunoreactivity. The current research indicates that ambroxol may possess senomorphic properties by impacting the transcription factors NF-κB and senescence-associated secretory phenotype (SASP). Consequently, it could provide neuroprotection through alterations in the Nrf2 and NF-κB signaling pathways in AD.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Novel SIRT3 Inhibitors for the Cancer Differentiation Therapy by Structural Modification","authors":"Honggang Li,&nbsp;Yanmei Du,&nbsp;Lihui Zhang,&nbsp;Guangzhao Xu,&nbsp;Fahui Li,&nbsp;Daopeng Zhang,&nbsp;Lei Zhang","doi":"10.1002/ddr.70016","DOIUrl":"10.1002/ddr.70016","url":null,"abstract":"<div>\u0000 \u0000 <p>Inhibition of SIRT3 triggered differentiation of multiple myeloma (MM) cells. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound <b>S27</b>. A total of 49 compounds divided into two series were designed and synthesized. In the enzyme inhibitory assay, several molecules (<b>A7</b>, <b>A13</b>, <b>B15</b>, and <b>B26</b>) exhibited potent SIRT3 inhibitory activity and selectivity. Significantly, representative compounds, especially <b>A7</b>, promoted differentiation of MM cells from cancer phenotype to normal cells, accompanied by increased expression of antigen CD49e, human immunoglobulin light chain λ-IgLG and κ-IgLG. Additionally, molecule <b>A7</b> reversed growth factor IL-6 induced MM cell proliferation, improved the antiproliferative activity of Ixazomib and increased the apoptotic rate of MM cells treated with Ixazomib. Collectively, potent SIRT3 inhibitors with MM cell differentiation potency were developed for the cancer therapy used alone or in combination.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KLF2 Inhibits Ferroptosis and Improves Mitochondrial Dysfunction in Chondrocyte Through SIRT1/GPX4 Signaling to Improve Osteoarthritis","authors":"Jiaqi Shi,&nbsp;Li Chen,&nbsp;Xu Wang,&nbsp;Xin Ma","doi":"10.1002/ddr.70015","DOIUrl":"10.1002/ddr.70015","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoarthritis (OA), a disease of articular joints, is the leading cause of disability in the elderly. Repressing ferroptosis and improving mitochondrial function can delay the progression of OA. Kruppel-like factor 2 (KLF2) exerts a protective effect on OA. However, whether KLF2 affects ferroptosis and mitochondrial function during OA remains unknown. The OA in vivo and in vitro models were constructed in this work. The structural damage of knee joint in OA mice was evaluated through Micro-CT scanning. H&amp;E, SOFG, TB, and TUNEL staining were applied for pathological examination of cartilage tissues. ELISA was employed to examine the contents of inflammatory factors. Additionally, iron deposition in cartilage tissues was measured by Prussian blue staining, and the levels of proteins related to ferroptosis were assessed by immunoblotting. Besides, mitochondrial morphology and function were estimated using a transmission electron microscope and JC-1 staining. In interleukin (IL)-1β-treated C28/I2 cells, the levels of inflammatory factors, intracellular ROS, mitochondrial ROS, lipid ROS, and Fe²⁺ were measured. Mitochondrial function was evaluated by detecting the levels of mitochondrial membrane potential (MMP), ATP, mPTP, and OCR. KLF2 overexpression ameliorated the structural damage of knee cartilage in OA mice. KLF2 upregulation inhibited ferroptosis and alleviated mitochondrial damage in knee cartilage of OA mice and IL-1β-treated C28/I2 cells. Moreover, KLF2 overexpression activated SIRT1/GPX4 signaling in vivo and in vitro. EX527 addition blocked the influences of KLF2 upregulation on ferroptosis and mitochondrial dysfunction in IL-1β-treated C28/I2 cells. Altogether KLF2 inhibits ferroptosis and improves mitochondrial dysfunction in chondrocytes through SIRT1/GPX4 signaling to improve OA.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Fatty Acid Metabolism, the Related Potential Biomarkers, and Targeted Therapeutic Strategies in Gastrointestinal Cancers","authors":"Ruixi Xie,&nbsp;Ying Luo,&nbsp;Bowen Bao,&nbsp;Xinshu Wu,&nbsp;Jia Guo,&nbsp;Jin Wang,&nbsp;Xiujuan Qu,&nbsp;Xiaofang Che,&nbsp;Chunlei Zheng","doi":"10.1002/ddr.70014","DOIUrl":"10.1002/ddr.70014","url":null,"abstract":"<div>\u0000 \u0000 <p>Gastrointestinal cancer has emerged as a significant global health concern due to its high incidence and mortality, limited effectiveness of early detection, suboptimal treatment outcomes, and poor prognosis. Metabolic reprogramming is a prominent feature of cancer, and fatty acid metabolism assumes a pivotal role in bridging glucose metabolism and lipid metabolism. Fatty acids play important roles in cellular structural composition, energy supply, signal transduction, and other lipid-related processes. Changes in the levels of fatty acid metabolite may indicate the malignant transformation of gastrointestinal cells, which have an impact on the prognosis of patients and can be used as a marker to monitor the efficacy of anticancer therapy. Therefore, targeting key enzymes involved in fatty acid metabolism, either as monotherapy or in combination with other agents, is a promising strategy for anticancer treatment. This article reviews the potential mechanisms of fatty acid metabolism disorders in the occurrence and development of gastrointestinal tumors, and summarizes the related potential biomarkers and anticancer strategies.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of ENO1 promotes autophagy dependent-ferroptosis and suppresses glycolysis in breast cancer cells via the regulation of CST1","authors":"Guoliang Huang,&nbsp;Lian Lu,&nbsp;Yuhong You,&nbsp;Jie Li,&nbsp;Kaixiang Zhang","doi":"10.1002/ddr.70004","DOIUrl":"10.1002/ddr.70004","url":null,"abstract":"<p>Autophagy-dependent ferroptosis and glycolysis play a significant role in tumor development. α-Enolase (ENO1), a glycolytic enzyme, has been demonstrated to function as a crucial modulator in breast cancer (BC). However, the specific mechanism by which ENO1 influences the ferroptosis and glycolysis of BC remains unclear. qRT-PCR, along with western blot analysis was applied to investigate ENO1 and cystatin SN (CST1) expression in BC cells. Glycolysis level was measured by extracellular acidification rate (ECAR), lactate production, glucose consumption, and western blot analysis. Ferroptosis was evaluated by iron and lipid peroxidation assay, DCFH-DA staining, and western blot analysis. Immunofluorescence, together with western blot analysis was adopted for assessing cell autophagy and mTOR signaling pathway. Cell apoptosis and Ki67 level were measured by TUNEL and immunohistochemistry, respectively. ENO1 had abundant existence in BC cell lines. ENO1 silencing inhibited glycolysis but promoted ferroptosis and autophagy. In addition, autophagy inhibitor 3-MA reversed the impacts of ENO1 silencing on glycolysis and ferroptosis. Meanwhile, mTOR activator MHY1485 demonstrated opposing effects on autophagy. Moreover, CST1 could be extensively found in BC cell lines, and its overexpression reversed the effects of ENO1 silencing on glycolysis and ferroptosis. In vivo experiments illustrated that ENO1 deletion suppressed BC tumor growth, increased the apoptosis rate, restrained cell proliferation, and glycolysis, but promoted ferroptosis and autophagy, as well as reducing CST1 and mTOR signaling. To sum up, ENO1 silencing mediated a utophagy-dependent ferroptosis and glycolysis in BC cells by regulating CST1.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARP7i Clinical Candidate RBN-2397 Exerts Antiviral Activity by Modulating Interferon-β Associated Innate Immune Response in Macrophages","authors":"Xiaoli Du,&nbsp;Jiawei Zhou,&nbsp;Yi Zhou,&nbsp;Yulong Chen,&nbsp;Yanhua Kang,&nbsp;Dongjiu Zhao,&nbsp;Xiang-Yang Ye,&nbsp;Liwei Wang,&nbsp;Tian Xie,&nbsp;Hang Zhang","doi":"10.1002/ddr.70013","DOIUrl":"10.1002/ddr.70013","url":null,"abstract":"<div>\u0000 \u0000 <p>Polyadenosine diphosphate-ribose polymerase 7 (PARP7) acts as a suppressor of the type I interferon (IFN) signaling pathway via suppressing TANK-binding protein 1 (TBK1). Research study indicates that inhibition of PARP7 could potentially regulate tumor immunity. However, the effect of PARP7 inhibition on innate antiviral immunity in macrophages as well as the underlying mechanism have not been demonstrated else well. We report herein that PARP7 inhibitor clinical candidate RBN-2397 could augment type I interferon (IFN-I) production in macrophages by elevating retinoic acid-inducible gene I (RIG-I) and stimulator of interferon genes (STING) signaling pathways. Treatment with RBN-2397 leads to increased pattern recognition ligands-induced interferon-β production in primary bone marrow-derived macrophages (BMDM) and RAW264.7 cells. Additionally, RBN-2397 suppresses viral replication efficiency in macrophages infected by vesicular stomatitis virus (VSV) and amplifies the expression of interferon-stimulated chemokine genes (ISGs). Mechanistically, RBN-2397 promotes TBK1 phosphorylation, consequently leading to the amplified activation of RIG-I and STING signaling pathways. Furthermore, RBN-2397 enhances the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 induced by IFN-α/β and the expression of chemokine genes in macrophages in response to IFN stimulation. In vivo experiments demonstrated that RBN-2397 enhances innate antiviral immunity in mice infected with VSV, resulting in increased serum IFN-β levels, reduced viral loads, and alleviated pulmonary inflammatory responses of the VSV-infected mice. In conclusion, our findings highlight the potential of RBN-2397 as a promising antiviral therapeutic agent for enhancing the IFN-relative antiviral immune defense in host.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}