Acta Pharmaceutica Sinica. B最新文献_第9页

Iron and siRNA co-encapsulated ferritin nanocages induce ferroptosis synergistically for cancer therapy

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.006

Danni Liu , Yaoqi Wang , Qi Sun , Dong Mei , Xiaoling Wang , Yan Su , Jie Zhang , Ran Huo , Yang Tian , Siyu Liu , Shuang Zhang , Chunying Cui

{"title":"Iron and siRNA co-encapsulated ferritin nanocages induce ferroptosis synergistically for cancer therapy","authors":"Danni Liu , Yaoqi Wang , Qi Sun , Dong Mei , Xiaoling Wang , Yan Su , Jie Zhang , Ran Huo , Yang Tian , Siyu Liu , Shuang Zhang , Chunying Cui","doi":"10.1016/j.apsb.2024.10.006","DOIUrl":"10.1016/j.apsb.2024.10.006","url":null,"abstract":"<div><div>Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the <em>in vitro</em> and <em>in vivo</em> results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 526-541"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Free fatty acid receptor-4 regulates T-cell-mediated allogeneic reaction through activating an aryl hydrocarbon receptor pathway

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.12.011

Maxwell Duah , Fei Zheng , Jingyi Shen , Yan Xu , Shuo Cao , Zhiling Yan , Qiu Lan , Ying Wang , Kailin Xu , Bin Pan

{"title":"Free fatty acid receptor-4 regulates T-cell-mediated allogeneic reaction through activating an aryl hydrocarbon receptor pathway","authors":"Maxwell Duah , Fei Zheng , Jingyi Shen , Yan Xu , Shuo Cao , Zhiling Yan , Qiu Lan , Ying Wang , Kailin Xu , Bin Pan","doi":"10.1016/j.apsb.2024.12.011","DOIUrl":"10.1016/j.apsb.2024.12.011","url":null,"abstract":"<div><div>Targeting T-cell is a strategy to control allogeneic response disorders, such as acute graft-versus-host disease (GVHD) which is an important cause of therapy-failure after allogeneic hematopoietic cell transplants. Free fatty acid receptor-4 (FFAR4) is a regulator of obesity but its role in T-cell and allogeneic reactions is unknown. Here, we found knockout of <em>Ffar4</em> in donor T-cells in a mouse allograft model increased acute GVHD whereas the natural FFAR4 ligands and the synthetic FFAR4 agonists decreased it. FFAR4 agonist-mediated anti-acute GVHD effects depended on FFAR4-expression in donor T-cells. The FFAR4 agonist CpdA suppressed donor T-cell-mediated alloreaction by activating an aryl hydrocarbon receptor (AhR) pathway. CpdA recruited <em>β</em>-Arrestin2 to FFAR4 which facilitated nuclear translocation of AhR and upregulation of IL-22. The CpdA-mediated anti-acute GVHD effect was absent in mice receiving <em>Ahr</em>-knockout or <em>Il22</em>-knockout T-cells. Recipient-expressing <em>Ffar4</em> was also important for the anti-acute GVHD effect of CpdA which inhibited activation of antigen presenting cells. Importantly, CpdA decreased acute GVHD in obese mice, an effect also depended on <em>Ffar4</em>-expression in donor T-cells and recipients. Our study shows the immunoregulatory effect of FFAR4 in T-cell, and targeting FFAR4 might be a relative option for controlling allogeneic reactions in obese patients.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 224-238"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulation of histidine metabolism by Lactobacillus Reuteri mediates the pathogenesis and treatment of ischemic stroke

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.003

Kangrui Hu , Zhihao Zhou , Haofeng Li , Jijun Xiao , Yun Shen , Ke Ding , Tingting Zhang , Guangji Wang , Haiping Hao , Yan Liang

{"title":"Regulation of histidine metabolism by Lactobacillus Reuteri mediates the pathogenesis and treatment of ischemic stroke","authors":"Kangrui Hu , Zhihao Zhou , Haofeng Li , Jijun Xiao , Yun Shen , Ke Ding , Tingting Zhang , Guangji Wang , Haiping Hao , Yan Liang","doi":"10.1016/j.apsb.2024.10.003","DOIUrl":"10.1016/j.apsb.2024.10.003","url":null,"abstract":"<div><div>Increasing evidence has underscored the significance of post-stroke alterations along gut–brain axis, while its role in pathogenesis and treatment of ischemic stroke (IS) remains largely unexplored. This study aimed to elucidate the therapeutic effects and action targets of <em>Panax notoginseng saponins</em> (PNS) on IS and explore a novel pathogenesis and treatment strategy of IS <em>via</em> profiling the microbial community and metabolic characteristics along gut–brain axis. Our findings revealed for the first time that the therapeutic effect of PNS on IS was microbiota-dependent. Ischemia/reperfusion (I/R) modeling significantly down-regulated <em>Lactobacilli</em> in rats, and PNS markedly recovered <em>Lactobacilli</em>, particularly <em>Lactobacillus reuteri</em> (<em>L.Reu</em>). Metabolomics showed a significant reduction in serum histidine (HIS) in clinical obsolete IS patients and rehabilitation period I/R rats. Meanwhile, the <em>L.Reu</em> colonization in I/R rats exhibited significant neuroprotective activity and greatly increased HIS in serum, gut microbiota, and brain. Moreover, exogenous HIS demonstrated indirect neuroprotective effects through metabolizing to histamine. Notably, vagus nerve severance in I/R rats was performed to investigate HIS's neuroprotective mechanism. The results innovatively revealed that PNS could promote HIS synthesis in gut by enhancing <em>L.Reu</em> proportion, thereby increasing intracerebral HIS through peripheral pathway. Consequently, our data provided novel insights into HIS metabolism mediated by <em>L.Reu</em> in the pathogenesis and treatment of IS.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 239-255"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.10.002

Yang Li , Yan Fang , Xiaoyu Chen , Linjiang Tong , Fang Feng , Qianqian Zhou , Shulun Chen , Jian Ding , Hua Xie , Ao Zhang

{"title":"Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer","authors":"Yang Li , Yan Fang , Xiaoyu Chen , Linjiang Tong , Fang Feng , Qianqian Zhou , Shulun Chen , Jian Ding , Hua Xie , Ao Zhang","doi":"10.1016/j.apsb.2024.10.002","DOIUrl":"10.1016/j.apsb.2024.10.002","url":null,"abstract":"<div><div>The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor <strong>13</strong> bearing a tetrahydrobenzofuro[2,3-<em>c</em>]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC<sub>50</sub> values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound <strong>13</strong> exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound <strong>13</strong> is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both <em>in vitro</em> and <em>in vivo</em>, thus making it worthy of further exploration.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 438-466"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Counteracting Alzheimer's disease via normalizing neurovascular unit with a self-regulated multi-functional nano-modulator 通过自调节多功能纳米调节器使神经血管正常化来对抗阿尔茨海默病

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 DOI: 10.1016/j.apsb.2024.05.017

Xue Xia , Ya Wei , Qianqian Huang , Yang Zhou , Xiaorong Wang , Yulong Shi , Xiaotong Yang , Wenqin Yang , Yiwei Zhang , Ting Lei , Yuan Huang , Hanmei Li , Meng Qin , Huile Gao

{"title":"Counteracting Alzheimer's disease via normalizing neurovascular unit with a self-regulated multi-functional nano-modulator","authors":"Xue Xia , Ya Wei , Qianqian Huang , Yang Zhou , Xiaorong Wang , Yulong Shi , Xiaotong Yang , Wenqin Yang , Yiwei Zhang , Ting Lei , Yuan Huang , Hanmei Li , Meng Qin , Huile Gao","doi":"10.1016/j.apsb.2024.05.017","DOIUrl":"10.1016/j.apsb.2024.05.017","url":null,"abstract":"<div><div>The neurovascular unit (NVU) is highly responsible for cerebral homeostasis and its dysfunction emerges as a critical contributor to Alzheimer's disease (AD) pathology. Hence, rescuing NVU dysfunction might be a viable approach to AD treatments. Here, we fabricated a self-regulated muti-functional nano-modulator (siR/PIO@RP) that can intelligently navigate to damaged blood-brain barrier and release therapeutical cargoes for synergetic AD therapy. The resulting siR/PIO@RP enables self-regulation of its distribution in accordance with the physio/pathological state (low/high RAGE expression) of the target site <em>via</em> a feedback loop. siR/PIO@RP is capable of performing intricate tasks and goes beyond the capabilities of single-target therapeutic agents utilized in AD therapy, such as reducing cerebral A<em>β</em> load, relieving neuroinflammation, and alleviating the dysfunction of NVU. Overall, the current study provides proof of concept that normalizing NVU holds promise as a means of alleviating AD symptoms.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5464-5478"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy 发现 RNA 去甲基化酶 FTO 的强效 PROTAC 降解剂，用于抗白血病治疗

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 DOI: 10.1016/j.apsb.2024.07.016

Lu Liu , Yuanlai Qiu , Yuying Suo , Siyao Tong , Yiqing Wang , Xi Zhang , Liang Chen , Yue Huang , Huchen Zhou , Hu Zhou , Ze Dong , Cai-Guang Yang

{"title":"Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy","authors":"Lu Liu , Yuanlai Qiu , Yuying Suo , Siyao Tong , Yiqing Wang , Xi Zhang , Liang Chen , Yue Huang , Huchen Zhou , Hu Zhou , Ze Dong , Cai-Guang Yang","doi":"10.1016/j.apsb.2024.07.016","DOIUrl":"10.1016/j.apsb.2024.07.016","url":null,"abstract":"<div><div>The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85—which potently inhibits FTO demethylation in AML cell lines—as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin–proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m<sup>6</sup>A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m<sup>6</sup>A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5382-5392"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141775573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria 纳米工程线粒体可通过替代功能障碍线粒体治疗眼部线粒体疾病

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 DOI: 10.1016/j.apsb.2024.08.007

Yi Wang , Nahui Liu , Lifan Hu , Jingsong Yang , Mengmeng Han , Tianjiao Zhou , Lei Xing , Hulin Jiang

{"title":"Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria","authors":"Yi Wang , Nahui Liu , Lifan Hu , Jingsong Yang , Mengmeng Han , Tianjiao Zhou , Lei Xing , Hulin Jiang","doi":"10.1016/j.apsb.2024.08.007","DOIUrl":"10.1016/j.apsb.2024.08.007","url":null,"abstract":"<div><div>Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, <em>PARKIN</em> mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I <em>via</em> mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I <em>via</em> an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5435-5450"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cover Story

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 DOI: 10.1016/S2211-3835(24)00427-1

引用次数: 0

Controlling tumor progression and recurrence in mice through combined treatment with a PD-L1 inhibitor and a designer Salmonella strain that delivers GM-CSF 通过联合使用 PD-L1 抑制剂和可提供 GM-CSF 的沙门氏菌株，控制小鼠的肿瘤进展和复发

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 DOI: 10.1016/j.apsb.2024.07.011

Heung Jin Jeon , Daejin Lim , EunA So , Solbi Kim , Jae-Ho Jeong , Miryoung Song , Hyo-Jin Lee

{"title":"Controlling tumor progression and recurrence in mice through combined treatment with a PD-L1 inhibitor and a designer Salmonella strain that delivers GM-CSF","authors":"Heung Jin Jeon , Daejin Lim , EunA So , Solbi Kim , Jae-Ho Jeong , Miryoung Song , Hyo-Jin Lee","doi":"10.1016/j.apsb.2024.07.011","DOIUrl":"10.1016/j.apsb.2024.07.011","url":null,"abstract":"<div><div>Combination therapy with checkpoint inhibitors blocks inhibitory immune cell signaling and improves clinical responses to anticancer treatments. However, continued development of innovative and controllable delivery systems for immune-stimulating agents is necessary to optimize clinical responses. Herein, we engineered <em>Salmonella</em> to deliver recombinant granulocyte macrophage colony stimulating factor (GM-CSF) in a controllable manner for combination treatment with a programmed death-ligand 1 (PD-L1) inhibitor. The engineered <em>Salmonella</em> enabled delivery of recombinant GM-CSF into mouse tumors, activating recruitment of immune cells, such as M1-polarized macrophages, dendritic cells, and CD8<sup>+</sup> T cells. Combination treatment with the PD-L1 inhibitor and engineered <em>Salmonella</em> increased the survival rate of tumor-bearing mice by 25%. New tumor growth was strongly suppressed, and visible tumors disappeared at 120 days post-infection (dpi) in mice rechallenged with additional tumor implantation at 100 dpi. The number of memory T cells increased >2-fold in tumor-rechallenged mice. Our findings demonstrate superiority of the engineered <em>Salmonella</em> as a cancer therapeutic agent with precise targeting ability, immune-boosting activity, and ease of combination with other therapeutics.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5479-5492"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141690009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of a novel exceptionally potent and orally active Nur77 ligand NB1 with a distinct binding mode for cancer therapy 发现一种新型特效口服活性 Nur77 配体 NB1，其独特的结合模式可用于癌症治疗

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-12-01 DOI: 10.1016/j.apsb.2024.07.012

Jun Chen , Taige Zhao , Wenbin Hong , Hongsheng Li , Mingtao Ao , Yijing Zhong , Xiaoya Chen , Yingkun Qiu , Xiumin Wang , Zhen Wu , Tianwei Lin , Baicun Li , Xueqin Chen , Meijuan Fang

{"title":"Discovery of a novel exceptionally potent and orally active Nur77 ligand NB1 with a distinct binding mode for cancer therapy","authors":"Jun Chen , Taige Zhao , Wenbin Hong , Hongsheng Li , Mingtao Ao , Yijing Zhong , Xiaoya Chen , Yingkun Qiu , Xiumin Wang , Zhen Wu , Tianwei Lin , Baicun Li , Xueqin Chen , Meijuan Fang","doi":"10.1016/j.apsb.2024.07.012","DOIUrl":"10.1016/j.apsb.2024.07.012","url":null,"abstract":"<div><div>The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable <em>in vivo</em> anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 12","pages":"Pages 5493-5504"},"PeriodicalIF":14.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141704479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0